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Pregnancy and childbirth are among the strongest risk factors for depression but the neurocognitive mechanisms underlying this enhanced risk are unknown. This study investigated emotional and non-emotional cognition in 57 pregnant women with or without an affective disorder during their third trimester, and the association between cognitive biases and subsequent postpartum depression (PPD). Of the pregnant women, 22 had a diagnosis of unipolar disorder (UD) and seven of bipolar disorder (BD) in full or partial remission, while 28 had no history of affective disorder. We included a control group of 29 healthy non-pregnant women. First, participants were interviewed, completed non-emotional and emotional cognitive tests and lastly filled out questionnaires. The participants were assessed two times after birth: at a home visit shortly after birth, and with a telephone interview to assess PPD in the first six months after birth. Healthy pregnant women rated infant cries less negatively than non-pregnant women, possibly reflecting preparation for motherhood. Pregnant women with UD exhibited a negative bias in ratings of infant cries, whereas pregnant women with BD showed a positive bias in ratings of infant happy faces and recognition of adult facial expressions. Across all pregnant women, more negative ratings of infant cries were associated with enhanced risk of PPD. Negatively biased perception of infant cries during pregnancy may thus signal vulnerability toward PPD.

Background There is no consensus regarding the impact of oncoplastic surgery (OPS) on rates of re‐excision and conversion to mastectomy following breast‐conserving surgery (BCS). Here these two outcomes after BCS and OPS were compared in a nationwide population‐based setting. Methods In Denmark, all OPS is registered and categorized into volume displacement, volume reduction or volume replacement. Patients who underwent BCS or OPS between 2012 and 2018 were selected from the Danish Breast Cancer Group database. Multivariable analyses were performed to adjust for confounders, and propensity score matching to limit potential confounding by indication bias. Results A total of 13 185 patients (72·5 per cent) underwent BCS and 5003 (27·5 per cent) OPS. Volume displacement was used in 4171 patients (83·4 per cent), volume reduction in 679 (13·6 per cent) and volume replacement in 153 (3·1 per cent). Re‐excision rates were 15·6 and 14·1 per cent after BCS and OPS respectively. After adjusting for confounders, patients were less likely to have a re‐excision following OPS than BCS (odds ratio (OR) 0·80, 95 per cent c.i. 0·72 to 0·88), specifically after volume displacement and reduction. The rate of conversion to mastectomy was similar after OPS and BCS (3·2 versus 3·7 per cent; P = 0·105), but with a lower risk in adjusted analysis (OR 0·69, 0·58 to 0·84), specifically after volume displacement and reduction procedures. Findings were similar after propensity score matching. Conclusion A modest decrease in re‐excision rate and less frequent conversion to mastectomy were observed after OPS compared with BCS., Compared with breast‐conserving surgery, oncoplastic surgery results in a modest decrease in re‐excision rates and less frequent conversion to mastectomy. Rates similar to breast‐conserving surgery only

Purpose Breast-contour preservation (BCP) is possible for most women treated for early-stage breast cancer. BCP can be defined as primary breast-conserving treatment (BCT), neoadjuvant chemotherapy (NAC) followed by BCT and immediate postmastectomy breast reconstruction (IBR). This study provides insight in current BCP strategies in Denmark and the Netherlands and aims to identify opportunities for improvement within both countries. Methods A total of 92,881 patients with early-stage breast cancer who were operated in Denmark and the Netherlands between 2012 and 2017 were selected from the Danish Breast Cancer Group and the Dutch National Breast Cancer Audit databases. BCP procedures and predictive factors were analyzed within and between both countries. Results BCP was achieved in 76.7% (n = 16,355) of the Danish and in 74.5% (n = 53,328) of the Dutch patients. While BCP rate did not change significantly over time in Denmark (p = 0.250), a significant increase in BCP rate from 69.5% in 2012 to 78.5% in 2017 (p Conclusions In more than 75% of all Danish and Dutch patients, surgically treated for early-stage breast cancer, the breast-contour was preserved. The different use of BCP strategies within Denmark and the Netherlands and the differences observed between hospitals in both countries emphasize the need for more (inter)national consensus on treatment modalities.

Background: Chromosome instability (CIN) in solid tumours is associated with poor prognosis and results in numerical and structural chromosomal aberrations. Our group previously have developed the CIN signatures and have demonstrated the CIN signatures as prognostic biomarkers in breast cancer cohorts. Furthermore, our work in the BR9601 and MA.5 clinical cohorts CIN4 provided level IIB evidence that CIN4 was predictive of anthracycline sensitivity. An analysis of the DBCG 89D clinical trial was now performed to validate the role of CIN gene expression signatures as a marker of anthracycline sensitivity. Methods: RNA was extracted from patients in DBCG 89D clinical trial analysed through NanoString technology. The prognostic and predictive values of the signatures on distant relapse-free survival (DRFS) were explored using Cox proportional hazard models. Multivariate models included menopausal status, tumour size, nodal status, ER and Her2 status, histological type and grade, and treatment regimen. Results: All of the 594 samples available from the DBCG 89D we successfully analysed. CIN25 and CIN70 gene expression signatures did not associate with any of the clinicopathological characteristics tested. In addition, CIN25 and CIN70 were not prognostic or predictive of distant relapse free or breast cancer specific survival in this clinical cohort. Low CIN4 score was associated with ER negativity (p=0.02), HER2 normal expression (p Conclusion: In this study we demonstrated that CIN4 was associated with aggressive disease. We were however in DBCG 89D unable to validate the predictive value of CIN4 concerning anthracycline sensitivity. Citation Format: Spears M, Jensen M-B, Lyttle N, Liao L, Laenkholm A-V, Ejitlertsen B, Bartlett JM. Validation of CIN4 in the DBCG 89D clinical cohort [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 P3-11-03.

Piezo- and ferroelectric thin films attract a lot of attention due to their wide range of applications including microsensors, microactuators, memory devices and use in high frequency electrical co...

Background: A growing body of evidence is suggesting that basal-like and triple negative breast cancers may be particularly sensitive to nucleoside analogues (gemcitabine, capecitabine). In a prospective-retrospective analysis of the phase III SBG0102 clinical trial randomizing metastatic breast cancer patients to gemcitabine plus docetaxel (GD) or to higher-dose single agent docetaxel (D), patients with basal-like breast cancer by PAM50 gene expression had significantly better overall survival (OS) in the gemcitabine arm. By immunohistochemistry (IHC), triple negative status was not predictive, but is a poor surrogate for the basal-like intrinsic subtype. More accurate IHC biomarkers have since become available defining basal-like breast cancers by nestin positivity or by loss of inositol polyphosphate-4-phosphate (INPP4b). Methods: Formalin-fixed paraffin embedded blocks of primary tumor tissue corresponding to 270 of the 337 patients participated in the SBG0102 trial were used to build tissue microarrays. IHC staining and interpretation for nestin and INPP4b by pathologists (who had no access to clinical data) followed published methods. A prespecified statistical plan was executed independently by Danish Breast Cancer Group statisticians, testing the primary hypothesis that patients with basal breast cancer – defined as positive for nestin or negative for INPP4b, regardless of ER/PR/HER2 status – would have superior OS on the GD treatment arm when compared to the D treatment arm by interaction test. Secondary outcomes included time to tumor progression (TTP) and response rate. Kaplan-Meier method with log-rank test of nestin and INPP4b status was used to measure OS and TTP. Forest plots were used to visualize predictive capacities relative to IHC markers and treatment effects. Results: Two hundred fifty two cases were evaluable for this study, among which 38 (15%) had been classified as basal-like, 45 (18%) as HER2-Enriched, 74 (29%) as luminal A and 91 (36%) as luminal B by PAM50. Among 241 cases being evaluable for both IHC nestin and INPP4b markers, positive staining of nestin or loss of INPP4b was observed in 43 (17%) of the total cases and was significantly associated with PAM50 basal-like subtype (p Conclusions: The nestin/INPP4b IHC panel offers a practical and inexpensive technology to identify basal-like patients. In the metastatic setting, women with IHC-basal breast cancers defined using these markers have superior overall survival when randomized to gemcitabine-containing chemotherapy compared to docetaxel alone. Citation Format: Asleh-Aburaya K, Lyck Carstensen S, Burugu S, Gao D, Tykjær Jørgensen CL, Won JR, Jensen M-B, Balslev E, Lænkholm A-V, Nielsen DL, Ejlertsen B, Nielsen TO. Basal biomarkers nestin and INPP4b predict gemcitabine benefit in metastatic breast cancer: Results from the phase III SBG0102 clinical 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 P2-10-02.

Background The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five yrs of adjuvant treatment with letrozole, tamoxifen, or their sequence in postmenopausal women with hormone-receptor–positive early breast cancer. The study is conducted by the International Breast Cancer Study Group (IBCSG) on behalf of BIG. 8010 patients (pts) were enrolled between March 1998 and May 2003, and first results demonstrating a significant DFS benefit favoring letrozole compared with tamoxifen were reported in 2005 at 25.8 months' MFU. Subsequent updates showed continuing DFS benefit and updated results published in 2011 at 8.1 yrs' MFU showed OS benefit. Industry-sponsorship of the original BIG 1-98 ended in 2010; IBCSG launched an observational, non-interventional long-term follow-up study (BIG 1-98 LTFU) to collect survival, disease status and adverse events for an additional 5 yrs. We report results from BIG 1-98 LTFU at 12 yrs' MFU. Methods The original trial includes the 8010 patients enrolled. The potential BIG 1-98 LTFU cohort consisted of 148 academic medical centers with a maximum of 6843 pts who were alive and continuing follow-up when the original study ended. Response bias was addressed using weighting class adjustments estimated using multivariable logistic regression. Unadjusted incidence rates are reported here per 1000 pt-yrs with 95% Poisson confidence intervals. An updated abstract will include adjusted incidence rates, as well as estimates of OS and DFS based on a weighted Kaplan-Meier approach. The database will close in July 2016. Results As of May 2016, 81 centers participated in the BIG 1-98 LTFU study, contributing data from approximately 3900 pts (57%) and extending MFU to 12 yrs. Compared with the potential cohort of 6843 pts, the ~3900 in the LTFU analytic cohort were more likely to be under age 65 yrs at enrollment, have node-positive disease, and have tumors that were < 2 cm, PgR positive (≥1%), and with no evidence of peritumoral vascular invasion. Extended adjuvant endocrine therapy for primary BC was continued in 2% of pts. Unadjusted incidence estimates of myocardial infarction increased during LTFU, while incidence of thromboembolic events and osteoporosis decreased (Table). Variations in incidence rates were noted depending on recording mechanism (e.g. registry, clinic visit, telephone, information from family). Unadjusted Incidence Rate/1000 pt-yrs (95% CI)Adverse EventDuring original studyDuring LTFUMyocardial Infarction1.7 (1.4-2.0)3.5 (2.7-4.5)Thromboembolic event6.0 (5.4-6.6)2.5 (1.8-3.3)Osteoporosis23.6 (22.5-24.9)18.2 (16.3-20.3)Bone fractures17.2 (16.2-18.3)15.0 (13.2-16.9) Overall 1845 deaths were reported; the unadjusted incidence of death was lower in the original study compared with during LTFU (21.9 vs. 26.6/1000 pt-yrs); incidence remained relatively stable for pts assigned to tamoxifen (24.9 vs. 25.2/1000 pt-yrs), and increased for pts assigned to letrozole (22.0 vs. 27.1/1000 pt-yrs). Conclusions The BIG 1-98 LTFU study has been successfully conducted. The additional data from the BIG 1-98 LTFU study provides important long-term clinical information about OS, DFS and adverse events. Citation Format: Thürlimann B, Giobbie-Hurder A, Colleoni M, Jensen M-B, Ejlertsen B, de Azambuja E, Neven P, Láng I, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Price K, Piccart-Gebhart M, Regan MM, Gelber RD, Coates AS, Goldhirsch A. 12 years' median follow up (MFU) of BIG 1-98: Adjuvant letrozole, tamoxifen and their sequence for postmenopausal women with endocrine responsive early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-05.

Background: The Prosigna (PAM50) risk of recurrence (ROR) score predicts 10yr DR in early breast cancer patients treated with ET alone (level 1 evidence). Invasive lobular breast cancer (ILBC) accounts for 10-15% of all breast cancer histological subtypes. Sporadic ILBC is characterized by somatic CDH1 mutations with loss of E-cadherin and a majority of low proliferative ER positive/HER2 negative tumors consistent with Luminal A subtype. Here we examine the ability of PAM50/ROR to predict 10yr DR in postmenopausal women who following a diagnosis of HR+ early ILBC were allocated to 5yr of ET alone. Methods: Using the population based clinical DBCG database FFPE primary tumor blocks, treatment, and follow-up data were collected from all patients diagnosed from 2000-2003 with HR+, postmenopausal EBC (N0-N1) who by nationwide guidelines were allocated to 5yr of ET alone, N=2,722 (1256 N0, 1466 N1). PAM50 intrinsic subtype classification (Luminal A, Luminal B, HER2-enriched, Basal-like) was conducted using the NanoString nCounter®Analysis System. Univariate and multivariate analyses tested the ability of PAM50 to predict DR. Patients were categorized as Low or High Risk based upon pre-specified ROR cutoff value of 40. HER2 positive tumors by immunohistochemistry were excluded from analysis. Results: Median follow-up was 9.25 years. Risk of 10yr DR by ROR and PAM50 (Luminal A and Luminal B) is shown in the table by ILBC as compared to invasive ductal breast cancer (IDBC) type. Cumulative incidence for 10 yr distant recurrence (DR)Histological subtypeRisk Group % [95% CI](N row%)Intrinsic Subtype % [95% CI](N row%)Histological subtype% [95% CI](N) LowHighLuminal ALuminal BAllDuctal3.8 [2.5-5.6] (738 35%)16.6 [14.4-18.8] (1388 65%)6.6 [5.1-8.4] (1174 59%)18.1 [15.2-21.3] (832 41%)12.1% [10.6-13.7] (2126)Lobular9.7 [5.5-15.4] (181 53%)23.9 [16.8-31.6] (159 47%)12.7 [8.6-17.8] (256 77%)24.1 [14.5-35.1] (77 23%)16.4 [12.2-21.1] (340) In this specific cohort the ILBC subgroup had a worse 10yr DR of 16.4% [12.2-21.1] as compared to IDBC of 12.1% [10.6-13.7] (Gray´s test, p = 0.046). A significant difference regarding the distribution of ILBC into both High and Low Risk Group and intrinsic subtypes as compared to IDBC was identified (p < 0.0001). Molecular intrinsic subtype analysis for ILBC by Prosigna (PAM50) showed DR 12.7 [8.6-17.8] for Luminal A vs 24.1 [14.5-35.1] for Luminal B. The difference between ILBC subtypes was not significant (p = 0.09). Adding ROR to a Fine and Gray's proportional sub-hazards model containing clinical and pathological variables significantly improved the model for ILBC, (likelihood ratio: p = 0.0001); HR for a 20-point change in ROR = 1.84 [1.37-2.48] notable with DR 9.7 [5.5-15.4] for the Low Risk Group. Conclusions: Following 5-yr of endocrine treatment alone patients with ILBC in this large population-based study had an inferior DR as compared to patients with IDBC and the apparent difference between ILBC and IDBC must be interpreted with caution. Citation Format: Laenkholm A-V, Jensen M-B, Buckingham W, Schaper C, Knoop A, Eriksen JO, Rasmussen BB, Ferree S, Haffner T, Kiboel T, Ejlertsen B. Prediction of 10yr distant recurrence (DR) using the Prosigna® (PAM50) assay in histological subgroups of a Danish breast cancer group (DBCG) cohort of postmenopausal Danish women with hormone receptor-positive (HR+) early breast cancer (EBC) allocated to 5yr of endocrine therapy (ET) alone [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 P1-07-10.

Background: The current standard method for locating nonpalpable breast lesions is wire guided localization (WGL) despite several methodological difficulties. Radioactive Seed Localization (RSL) has been developed to reduce these difficulties. The aim of this randomized trial was to compare the rate of positive resection margins between RSL and WGL in patients with nonpalpable invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS). Material and Methods: Patients with nonpalpable IBC or DCIS visible on ultrasound were randomized to either of the two localization methods. Primary outcome was margin status at the final pathological evaluation. According to Danish standard in the study period margins were defined positive if cancer cells were found < 2mm from the inked margin. Secondary outcomes were duration of the surgical procedure, weight of the excised specimen and patient's pain perception. χ2-test, Fisher's exact test and Wilcoxon rank-sum test, respectively, were used to test differences between groups. Level of statistical significance was set to 5%. The average activity of seeds used in the trial was 1.70 MBq (range 0.7-3.27). Results: 413 cases representing 409 patients were randomized; 207 were allocated to RSL and 206 to WGL. 23 cases, who did not meet inclusion criteria, chose to withdraw, or had a change in surgical management, were excluded. The remaining 390 were included in the analysis. Patient, surgical and pathological characteristics between the two groups were alike, except for significantly more patients with DCIS in the WGL group (5.1% vs 0.5%). Significantly more cases in the WGL group (9.7%) needed additional localization compared to the RSL group (2.1%) (p=0.0014). In all cases but one in the RSL group, the index lesion was removed. Margins were positive in 23 cases (11.8%) in the RSL group compared to 26 cases (13.3%) in the WGL group. We were not able to detect a difference in margin status between the two groups (p=0.65). For IBC only, the number of positive margins was 22 (11.3%) in the RSL group and 21 (11.4%) in the WGL group (p=0.997). There was no difference between the two groups in the amount of tissue removed whether the analysis was done on the primary excision (p=0.18) or the total weight including intraoperative re-excisions (p=0.33). There was no difference in pain perception between the two groups whether patients who received local anesthesia were kept in the analysis (p=0.28) or excluded (p=0.91). Local anesthesia was used more frequently in the RSL group. Finally, there was no difference in the duration of the surgical procedure (p=0.12), the complication rate (p=0.89) or the identification rate for SN (p=1.0). Conclusions: We were not able to detect any differences considering positive margins, patient's pain perception or duration of the surgical procedure between the two localization methods. However, RSL offers a major logistic advantage, as the seed localization can be done several days before surgery without any risk or discomfort for the patient, with a low proportion of patients needing additional localization. So the RSL procedure has now been found preferable at our institutions. Citation Format: Langhans L, Tvedskov TF, Klausen TL, Jensen M-B, Talman M-L, Vejborg I, Benian C, Roslind A, Hermansen J, Oturai PS, Bentzon N, Kroman N. Radioactive seed localization versus wire guided localization of nonpalpable invasive and in situ breast cancer: A Danish multicenter randomized controlled trial [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 S3-08.

Introduction: Reproductive history and breast cancer risk reportedly differ by the estrogen receptor (ER±) and by the joint expression of ER and the human epidermal growth factor-2 receptor (ER±/HER2±). However, large sample sizes are needed to identify risk factor associations for the relatively less common ER- subtypes. Material and Methods: We, therefore, linked two large-scale and population-based Danish registries to assess the associations for parity, number of live births, and age at first live birth (AFLB) with receptor-specific breast cancer risk. Relative risks (RRs) and 95% confidence intervals (CIs) for associations were estimated with Poisson regression models. Results: With nearly 31 million women-years of follow-up, there were 45786 Danish women between the ages 20-84 years who developed an invasive breast cancer during the study period 1992-2011. Parity significantly reduced risk for ER+ and ER+/HER2- subtypes (RR for ER+/HER2- = 0.92; 0.87, 0.98) and suggestively increased risk for ER- and ER-/HER2- subtypes (RR for ER-/HER2- = 1.16; 0.99, 1.36). RRs increased with advancing AFLB for ER+ cancers, especially among premenopausal women; and were elevated for ER- cancers among age groups 12-19 years and 30-34 years compared to the reference age group 20-24 years. Conclusion: Associations of breast cancer risk and reproductive history varied among Danish women by ER± and by ER±/HER2±, consistent with receptor-specific etiological heterogeneity. Risk estimates for ER+ and ER+/HER2- cancers were similar to the well-established associations for breast cancer overall, whereas relative risks for ER- and ER/HER2- cancers tended to be null or the inverse of ER+ associations. Citation Format: Anderson WF, Pfeiffer RM, Wohlfahrt J, Ejlertsen B, Jensen M-B, Kroman NT. Reproductive factors and subtype specific breast cancer risk. [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 P1-07-03.

Background: HR+EBC patients are routinely treated with both adjuvant radiation therapy (RT) and ET. RT is considered an important tool for achieving local control of disease. A limited number of biomarkers have been demonstrated to predict LR. In a previously performed retrospective analysis of a randomized trial, Prosigna (PAM50) risk of recurrence (ROR) score identified low risk patients with a local recurrence rate of 1.6% at 9.5yr median follow-up. In this study, we seek to validate the ability of ROR to predict LR in a comprehensive nationwide cohort from Denmark. Methods: Using the population based DBCG database primary FFPE tumor blocks and follow-up data were collected from all postmenopausal Danish women diagnosed from 2000-2003 with HR+EBC (N=2,722). Prosigna (PAM50) on the NanoString nCounter® Dx Analysis System assigned each patient an ROR score and associated risk group based on pre-specified cutoffs. Patients are also assigned an intrinsic subtype (Luminal A, Luminal B, Her2-Enriched, Basal-Like) based on gene expression. Univariate and multivariate analyses were performed to assess the ability of Prosigna (PAM50) to predict LR. Results: 48 local recurrences were observed with median follow-up of 9.25 yr. Continuous ROR was significantly associated with LR in univariate and multivariate models including node status (0, 1, 2, or 3 positive nodes), tumor size (≤2 vs.>2cm), grade (I, II, III, or unknown), age (≤65 vs.>65yr), and local treatment (mastectomy (MX), lumpectomy+RT, or MX+RT) (p=0.036 and p=0.049, respectively). Clinicopathologic variables were not significant in the multivariate model alone or in combination (p=0.85 for full model excluding ROR). Utilization of a pre-specified LR cutoff, hazard ratio (HR) and [95%CI, p-value] for high risk vs. low risk patients in a univariate analysis was 1.96 [1.11-3.46, p=0.0205] and 2.04 [1.08-3.83, p=0.0275] in the multivariate analysis. 10-year cumulative incidence of LR for low risk patients was 1.7% [1.1%-2.6%]. Similarly, 10-year cumulative incidence of LR for Luminal A patients was 1.7% [1.1%-2.6%]. 10-year cumulative incidence for high risk patients was 2.3% [1.3%-3.2%]. Conclusions: In a large population-based study of n=2,722 patients, Prosigna (PAM50) predicted LR over standard variables. These data validate a pre-specified cutoff separating patients at high and low risk of LR. Additional studies of Prosigna (PAM50) in RT-untreated populations are ongoing. Citation Format: Ole Eriksen J, Jensen M-B, Laenkholm A-V, Kibøll T, Bruun Rasmussen B, Knoop AS, Ferree S, Haffner T, Buckingham W, Schaper C, Ejlertsen B. Validation of prediction of local recurrence (LR) by Prosigna® (PAM50) in a Danish breast cancer cooperative group (DBCG) cohort of hormone receptor positive (HR+), postmenopausal early breast cancer (EBC) patients allocated to 5yr of endocrine therapy (ET). [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 P2-08-10.

Aim: To determine the predictive value of intrinsic subtypes for response to adjuvant chemotherapy using specimens from a randomized clinical trial. Background: Several studies have shown distinct clinical profiles of intrinsic breast cancer subtypes. The Luminal A subtype has a favorable prognosis with higher survival rate and lower recurrence in comparison to other breast cancer subtypes (luminal B, HER2 and basal-like). In addition, there is mounting evidence suggesting that intrinsic breast cancer subtypes differ in their responsiveness to adjuvant chemotherapy. Based on these data, we hypothesized that Luminal A breast cancer patients derive no benefit from adjuvant chemotherapy whereas other intrinsic subtypes do. Randomized breast cancer trials with a no chemotherapy arm and available tissues are rare, but represent the best materials to test for markers predicting chemotherapy benefit. The 77B clinical trial from the Danish Breast Cancer Cooperative Group (DBCG) offers a unique opportunity to test such hypotheses as it randomized 1146 premenopausal women, who had positive axillary lymph nodes or tumors >5 cm, to two chemotherapy arms (single-agent oral cyclophosphamide, or cyclophosphamide-methotrexate-fluorouracil (CMF)), and two no chemotherapy arms (levamisole, or no agent). All arms included radiotherapy but no endocrine therapy. Methods: We performed a full intrinsic subtype analysis on the 709 breast cancers available from DBCG77B on tissue microarrays using previously published, locked-down immunohistochemical (IHC) methods and intrinsic subtype definitions based on ER, PR, HER2, Ki67 and basal markers (Prat et al. JCO 2014). Biomarker scoring was performed in Vancouver by researchers with no access to the clinical database. A full statistical plan was prespecified in the Material Transfer Agreement and executed accordingly by the DBCG Statistical Office. 10-year invasive disease-free survival (IDFS) was the primary end point in DBCG77B; overall survival was also a predefined endpoint. The primary hypothesis was to assess interaction between benefit of chemotherapy (chemotherapy yes vs no) and subtype (Luminal A vs non-luminal A). This was analyzed in multivariate Cox proportional hazards models using the Wald test for interaction. Results: 709 patients had tissue available and completed IHC intrinsic subtyping. The effect of chemotherapy in this subset of patients was similar to the original trial: hazard ratio 0.56, favoring chemotherapy for 10-yr IDFS. IHC classified 165 as luminal A, 319 luminal B, 58 HER2E and 91 as triple negative (including 82 core basal). Patients with luminal A breast tumors did not benefit from chemotherapy (HR = 1.07, 95% CI = 0.53-2.14, p = 0.86), whereas patients with non-luminal A subtypes did (HR = 0.50, 95% CI = 0.38-0.66, p < 0.001). This heterogeneity was statistically significant (p=0.048). A similar trend for 25-yr OS was seen, although not significant. Conclusions: In a formal prospective-retrospective analysis of the DBCG 77B study randomizing women to adjuvant cyclophosphamide-based chemotherapy vs. no chemotherapy arms, patients with non-luminal A breast tumors (defined by IHC), but not luminal A tumors, benefit from adjuvant chemotherapy. Citation Format: Nielsen TO, Jensen [lrm] M-B, Gao D, Leung S, Burugu S, Liu S, Tykjær Jørgensen CL, Balslev E, Ejlertsen B. High risk premenopausal luminal A breast cancer patients derive no benefit from adjuvant chemotherapy: Results from DBCG77B randomized 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 S1-08.

BACKGROUND: This study evaluates persistence and severity of docetaxel-induced neuropathy (peripheral neuropathy (PN)) and impact on health related quality of life in survivors from early-stage breast cancer.METHODS: One thousand and thirty-one patients with early-stage breast cancer, who received at least one cycle of docetaxel and provided information on PN during treatment, completed questionnaires on PN as an outcome (Common Toxicity Criteria (CTC) scores, European Organisation for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC CIPN20) and EORTC Quality of Life Questionnaire (QLQ)-C30) after 1-3years.FINDINGS: Upon completion of docetaxel treatment, 241 patients (23%) reported PN, grades 2-4. PN persisted for 1-3years among 81 (34%) while PN regressed to grades 0-1 among 160 (66%). Among 790 patients (77%) without PN, 76 (10%) developed PN 1-3years later while 714 (90%) stayed free from PN. Significant risk factors for persistent PN were age ⩾55 (p=0.001), maximum grade of PN during docetaxel treatment (pINTERPRETATIONS: Overall, 15% of breast cancer survivors treated with docetaxel report PN 1-3years after treatment with a significant negative impact on HRQOL.

PURPOSE: The DBCG 77C trial compared one year of tamoxifen in postmenopausal, steroid-receptor unknown, high-risk breast cancer patients to no adjuvant systemic therapy. After a potential follow-up of 30 years we report overall efficacy for the study and results according to subtypes subsequently assessed by immunohistochemistry and FISH. METHODS: Between 1977 and 1982, 1716 postmenopausal patients with tumors larger than 5 cm or positive axillary nodes were randomly assigned to no systemic therapy or tamoxifen 30 mg daily for one year. The main study is reported as an ITT analysis with the predefined DFS and BCM as endpoint. For multivariate analysis the Cox proportional hazards regression model was applied to assess the adjusted hazard ratio of treatment regimen, and to explore interactions. Formalin-fixed, paraffin-embedded primary breast tumor tissue blocks were available from 1548 (90%) of the 1716 participants enrolled and 1428 were assessable for ER, PR, HER2 and Ki67. The hormone receptor positive (ER and/or PR) cancers were defined as luminal A if Ki67 low and HER2-negative; as luminal B if Ki67 high or HER2-positive; and otherwise as HER2 positive or triple negative. RESULTS: In the intent-to-treat (ITT) population one year of tamoxifen improved the disease-free-survival (DFS) (Hazard ratio (HR) = 0.87; 95% CI 0.77-0.98), the recurrence-free-survival (RFS) (HR = 0.79; 0.69-0.90) and reduced the breast-cancer-specific-mortality (BCM) (HR = 0.83; 0.73-0.93). Recurrence-free survivals were improved significantly by tamoxifen in luminal A (HR = 0.66; 0.53-0.84) and luminal B/HER2- (HR = 0.54; 0.39-0.74) but not in the other subsets, and with similar results for BCM with 30 years follow-up. CONCLUSION: One year of treatment with tamoxifen significantly improves RFS and BCM in postmenopausal patients with ER positive breast cancers. The benefit from tamoxifen was not significantly different in luminal A and B subtypes. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-03.

Purpose: HER2 amplification, TOP2A aberrations and absence of TIMP-1 (Tissue Inhibitor of Metalloproteinase-1) expression in breast carcinomas have been associated with incremental benefit from anthracycline-containing adjuvant chemotherapy in several reports. In the DBCG 89D trial, we demonstrated that the predictive value of these markers improved when they were combined in a profile and the present study was undertaken to validate these findings in NCIC CTG MA.5, a similar but independent clinical trial. Design: TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to CEF or CMF in the MA.5 trial. Patients were classified according to 2 predefined marker profiles — the HT profile (HER2, TIMP-1) and the 2T profile (TOP2A, TIMP-1) and the statistical analyses were performed as closely as possible to the analytical approach used previously in the MA.5 trial and when analysing the biomarker profiles in the DBCG 89D trial. Results: 98 (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. 44% of patients were classified as HT responsive (HER2-positive and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT responsive patients, CEF was superior to CMF with improved RFS (adjusted HR, 0.64; 95% CI, 0.42 to 0.98) and a borderline-significant improvement in OS (adjusted HR, 0.66; 95% CI, 0.42 to 1.04). A significant HT profile versus treatment interaction was detected for OS (P=0.03). In 2T responsive patients, CEF was superior to CMF with borderline significant improvement in RFS (adjusted HR, 0.67; 95% CI, 0.43 to 1.03), and with improvement in OS (adjusted HR, 0.58; 95% CI, 0.36 to 0.93). A significant 2T profile versus treatment interaction was detected for OS (P=0.01). Conclusion: In the MA.5 trial, we have validated the HT and 2T profiles as predictors of incremental benefit from anthracycline-containing chemotherapy. The proportion of patients categorized as anthracycline responsive increases from 18–27% using individual markers to 37–44% when combining TIMP-1 with either HER2 or TOP2A. Patients with responsive profiles had a 34–42% relative reduction in mortality when treated with CEF. In contrast, patients with non-responsive profiles (56-63% of patients) had no incremental benefit from CEF compared with CMF. All 3 biomarkers are easily applied in the pathology lab and as such could be used in daily clinical practice to select patients for anthracycline or non-anthracycline containing adjuvant chemotherapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-07.

Housing calves in large groups is associated with a higher risk of respiratory disease and with increased difficulties in identifying diseased animals compared with single housing. The aim of the present study was to investigate the effect of clinical disease on some behaviors recorded by automatic milk feeders in pre-weaned dairy calves. The experiment included 27 calves from a Danish research farm and 41 calves from a Swedish research farm. The calves were fed restrictively from a computer-controlled milk feeder, and all calves were subjected to daily clinical examinations for 3 to 26 d, with information gathered on general condition, nasal discharge, lung auscultation findings, coughing, signs of dehydration, naval status, rectal temperature, fecal consistency, and presence of chin abscess, arthritis, umbilical hernia, poor body condition, and poor hair coat. Calves suffering from diarrhea, respiratory disease, fever, or unspecific decreased general condition for more than 2 d were considered to be diseased and were declared to have recovered when they had been free of clinical signs of the disease for at least 2 d. The effects of clinical status (healthy, diseased) on the number of rewarded and unrewarded visits to the calf feeder and drinking rate, respectively, were analyzed by variance component analysis using a mixed model. Milk consumption on diseased and nondiseased days within calves was compared using a Wilcoxon signed rank test. In total, 53 of the calves were diagnosed as diseased during the study period. All cases of diseases were mild and were associated with an unaffected or only mildly affected general condition. Diarrhea was diagnosed in 51 calves, 6 of which also had respiratory disease. In 2 calves, respiratory disease was the only diagnosis. Eleven calves had an unspecific decreased general condition. The number of unrewarded visits was significantly reduced when calves were diseased. In Swedish calves, there was also a tendency for rewarded visits to be reduced during diseased days. Drinking rate and number of rewarded visits increased with increasing age. No effect of clinical status on milk consumption was detected. The number of unrewarded visits was the most sensitive of the 4 feeding behaviors monitored to indicate clinical disease in calves fed restricted milk volumes.

Background Gabapentin (GAB) has recently been introduced for postoperative pain treatment in orthopedic surgery. As persistent postoperative pain is still a major problem in total knee arthroplasty (TKA), studies on the effect and side effects of Gabapentin in addition to the commonly used morphine (MOR), Oxynorm (OXY) and Norspan (NOR) are highly warranted. In the present study, four relevant treatment algorithms, gabapentin and morphine (GAB/MOR), gabapentin and Oxynorm (GAB/OXY), Oxynorm (OXY) and Gabapentin, Oxynorm and Norspan (GAB/OXY/NOR) were examined. Patients and methods A total of 241 patients were followed systematically during one month following TKA in four consecutive series: 60 patients were treated with GAB/MOR, 62 patients with GAB/OXY, 59 patients with OXY, and 60 patients with GAB/OXY/MOR. On the day before surgery and on postoperative day 1, 14, and 30, pain during rest, pain during walking and side effects (constipation, dizziness, and nausea) were reported (VAS). Results After 30 days, pain greatly decreased in all groups, with a superior effect of GAB/OXY/NOR for pain during rest and only slightly more side effects at day 1. Conclusions In management of postoperative pain following TKA, data indicated that GAB/OXY/NOR was superior, compared to GAB/MOR, GAB/OXY, and OXY.

Following modified radical mastectomy, pre- and perimenopausal (amenorrhoea for5 years) patients with stage II or III breast cancer received CMF (cyclophosphamide 600, methotrexate 40, 5-fluorouracil 600 mg/m2 intravenously (i.v.) every 4 weeks, 9 cycles). The effect on recurrence-free survival (RFS) and overall survival (OS) of the addition of adjuvant tamoxifen (TAM) to adjuvant chemotherapy was examined by randomisation either to no additional treatment (n = 314), or concurrently TAM 30 mg daily for 1 year (n = 320). 40% had positive, 12% negative and 48% unknown receptor status. One year after surgery 21% versus 35% (CMF + TAM versus CMF) were still menstruating (P0.01). With a median follow-up of 12.2 years there was no difference in RFS (10-year RFS 34% versus 35%, P = 0.81) or OS (45% versus 46%, P = 0.73). In a Cox proportional hazards model, tumour size, number of metastatic lymph nodes, frequency of metastatic nodes in relation to total number of nodes removed, degree of anaplasia, age, and menostasia within the first year after operation were significant independent prognostic factors for RFS, and the same factors except age for OS. No significant interactions with TAM were seen. Thus, in this group of pre- and perimenopausal high-risk early breast cancer patients with heterogeneous receptor status given CMF i.v., concurrent TAM for 1 year did not improve the outcome. These results do not exclude that receptor positive patients may benefit from adjuvant TAM for longer periods given sequentially to chemotherapy.

Background: DBCG 07-READ was designed to compare sequential EC followed by D with DC in patients with early, TOP2A normal breast cancer as a retrospective evaluation of the DBCG 89D trial suggested that these patients would not benefit from an anthracycline. Methods: This is a multicenter open-label randomized phase III trial. Three groups of women were eligible following completely resected unilateral invasive TOP2A normal (TOP2A gene to centromere 17 ratio of 0.8 to 2.0) breast cancer by mastectomy or breast conserving surgery in combination with axillary clearance or a negative sentinel node biopsy; 1: Age 18 to 39 years; 2: Age 40 to 75 years and estrogen receptor (ER) negative ( 20 mm. Eligible patients were required to have a Charlson Comorbidity (CC) Index < 2 and to be without signs of distant metastasis. Patients were randomized to receive 6 cycles of DC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2) every 3 weeks or 3 cycles of EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2) followed by 3 cycles of D (docetaxel 100 mg/m2) every 3 weeks. In case of a CC Index of 1 or 2 chemotherapy was administered at a reduced dose-intensity. Adjuvant endocrine treatment, trastuzumab and radiotherapy were administered according to the guidelines of the DBCG. The primary endpoint was disease-free survival (DFS), and secondary endpoints were overall survival (OS) and distant disease-free survival (DDFS). Results: Between July 2008 and December 2012 we (12 DBCG centers) randomly assigned 2006 eligible patients to DC (N=1008) or EC-D (N=998). Patient and tumor characteristics were balanced by treatment groups. The median estimated potential follow-up is 5.4 years and the 5-year DFS was 88.0%; 95% CI 85.8 to 90.0 in the EC-D arm and 87.9%; 95% CI 85.7 to 89.9 in the DC arm. No significant difference in the risk of DFS events HR=1.03; 95% CI 0.80 to 1.32; p=0.84 or mortality HR=1.11; 95% 0.79 to 1.56; p=0.55 was observed in the intent to treat analysis. Patient-reported toxicity will be compared for the two chemotherapy regimens. Conclusion: The READ trial gives evidence to support no outcome benefit from anthracycline in patients with TOP2A normal ealy breast cancer. Citation Format: Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer [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 S6-03.

This study evaluated the reproducibility of measuring lean tissue mass (LTM), fat mass(FM(DXA)), bone mineral content (BMC) and density (BMD) with a Hologic QDR-2000 DXA scanner, and both fat free mass (FFM(bio)) and fat mass (FM(bio)) with an impedance meter. Furthermore, the study aimed to assess whether sheets and pillows significantly altered the DXA results. Fifty-one healthy volunteers aged 20-61 years were examined before and after repositioning (n = 20), removal of the sheets (n = 10), addition of two foam pillows (n = 11) or a regular pillow (n = 10). One to 7 days later a re-examination was performed (n = 35). Eight surgical patients were also scanned twice 1-7 days apart. The day to day coefficients of variation were about 1% for most measurements, though more than 2% for FM(DXA), and FM(bio). For total tissue mass, LTM, and BMC there was a significant biological day to day variance whereas for the other measurements the day to day variation could be accounted for by just measurement variance. Pillows systematically changed the estimates of bone mineral and soft tissue, but sheets did not.

We estimated the impact of axillary lymph node dissection (ALND) on the risk of axillary recurrence (AR) and overall survival (OS) in breast cancer patients with micrometastases or isolated tumor cells (ITC) in sentinel nodes. We used the Danish Breast Cancer Cooperative Group (DBCG) database to identify patients with micrometastases or ITC in sentinel nodes following surgery for primary breast cancer between 2002 and 2008. A Cox proportional hazard regression model was developed to assess the hazard ratios (HR) for AR and OS between patients with and without ALND. We identified 2074 patients, of which 240 did not undergo further axillary surgery. The 5-year cumulated incidence for AR was 1.58 %. No significant difference in AR was seen between patients with and without ALND. The age adjusted HR for AR if ALND was omitted was 1.79 (95 % CI 0.41–7.80, P = 0.44) in patients with micrometastases and 2.21 (95 % CI 0.54–8.95, P = 0.27), in patients with ITC after a median follow-up of 6 years and 3 months. There was no significant difference in overall survival between patients with and without ALND, when adjusting for age, co-morbidity, tumor size, histology type, malignancy grade, lymphovascular invasion, hormone receptor status, adjuvant systemic treatment and radiotherapy, with a HR for death if ALND was omitted of 1.21 (95 % CI 0.86–1.69, P = 0.27) in patients with micrometastases and 0.96 (95 % CI 0.57–1.62, P = 0.89) in patients with ITC after a medium follow-up on 8 and 5 years. In this nationwide study, we found a low risk of AR on 1.58 % and we did not find a significantly increased risk of AR if ALND was omitted in patients with micrometastases or ITC in sentinel nodes. Furthermore, no significant difference in overall survival was seen between patients with and without ALND when adjusting for adjuvant treatment.

Background: It is shown that isolated tumor cells are more common in the sentinel node after needle biopsy of a breast cancer, indicating iatrogenic displacement of epithelial cells. This may result in unnecessary axillary lymph node dissections. It is possible that a similar iatrogenic displacement occurs after surgical excision biopsy but the incidence and clinical significance is basically unknown. Material and Methods: By linking data from the Danish Breast Cancer Cooporative Group database and data from the Danish National Health Registry we compared the incidence of isolated tumor cells and micrometastases in the sentinel node of 347 breast cancer patients with prior surgical excision biopsy to a group of 14401 patients without prior surgical excision biopsy in a multivariate analysis adjusting for tumor size, receptor status, type and histological grade. The incidence of isolated tumor cells in the sentinel node was further analysed by histological type. Finally, we investigated the incidence of non-sentinel node metastases in patients with isolated tumor cells and micrometastases in the sentinel node after prior surgical excision biopsy. Results: We found an adjusted odds ratio on 3.99 (95% CI 2.67-5.97; P Conclusions: The 4-fold increase in isolated tumor cells in the sentinel node after surgical excision biopsy indicates that this procedure induces iatrogenic displacement of epithelial cells. This displacement is more common in ductal carcinomas, despite the fact that lobular carcinomas, in general, are more likely to present with isolated tumor cells in the sentinel node. We found no further dissemination to non-sentinel lymph nodes, suggesting that isolated tumor cells in the sentinel node in these women do not indicate further spread of disease. Hence, in case of isolated tumor cells in the sentinel node after prior surgical excision biopsy, omission of axillary lymph node dissection should be considered. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S5-2.

597 Background: HER-2, TOP2A, and TIMP-1 have shown predictive properties regarding benefit from anthracyclines in patients with breast cancer. In the present study, TIMP-1 IHC was integrated with TOP2A FISH and HER-2 status in two separate profiles. Methods: The DBCG 89-D trial randomized 980 high-risk Danish breast cancer patients to nine series of CMF or CEF. CEF was superior to CMF in terms of DFS and OS (Ejlertsen et al, EJC 2007). HER-2 status and TOP2A copy number changes were determined as described previously (Knoop et al, J Clin Oncol. 2005). TMA s were constructed and analyzed centrally for TIMP-1 expression by IHC (± tumor cell immunoreactivity). TIMP-1 was combined with HER-2 into a joint HT marker (HT-non-responsive (HT-NR): HER-2 normal and TIMP-1 positive or HT-responsive (HT-R): HER-2 positive and/or TIMP-1 negative) and with TOP2A into a joint 2T marker (2T-NR: TOP2A normal and TIMP-1 positive or 2T-R: TOP2A abnormal and/or TIMP-1 negative). Relationships between IDFS, OS and the HT/2Tprofiles were analyzed using multivariate regression analysis. Results: Among patients with a HT-R profile CEF was superior to CMF in terms of both invasive disease-free survival (IDFS) (HR 0.62; 95% CI 0.45–0.86; p = 0.004) and overall survival (OS) (HR 0.63; 95% CI, 0.45–0.87; p = 0.005). In patients with a HT-NR profile, no significant differences between CEF and CMF were demonstrated for IDFS or OS. A significant HT profile (HT-R or HT-NR) versus treatment (CEF or CMF) interaction was detected by the Wald-test for both IDFS (p = 0.036) and OS (p = 0.047). An even more pronounced separation was observed regarding the 2T profile, and in patients with a 2T-R profile treatment with CEF was superior to CMF in terms of IDFS (HR 0.48; 95% CI 0.34–0.69; p < 0.001) and OS (HR 0.54; 95% CI, 0.38–0.77; p < 0.001). No significant difference was observed in patients with a 2T-NR profile. A highly significant 2T profile versus treatment interaction was detected for IDFS (p < 0.001) and OS (p = 0.004). Conclusions: Profiles created by joining TIMP-1 with either HER-2 status or TOP2A gene status seems advantageous compared to the use of a single marker. [Table: see text]

Abstract #36 Background: Anthracyclins are potent poisons for topoisomerase II, an indispensable enzyme for DNA replication, repair and transcription. Apoptosis is often the consequence of anthracycline induced DNA breaks but cancer cells may escape through activation of the cell survival pathway by Tissue Inhibitor of Metalloproteinases-1 (TIMP-1). The aim of the present study was to determine the predictive value of the combination of the two biomarkers (TOP2A and TIMP-1) for benefits observed with CEF compared to CMF in DBCG trial 89D. Material and Methods: The DBCG 89-D trial randomized 980 high-risk Danish breast cancer patients to nine series of CMF or CEF, without endocrine therapy. Overall CEF was superior to CMF in terms of DFS and OS (Ejlertsen et al, EJC 2007). TOP2A copy number changes were determined with the TOP2A FISH pharmDx™ Kit (Dako A/S, Glostrup) as described previously (Knoop et al, JCO 2005). TMAs were constructed and analyzed centrally for TIMP-1 expression using the anti-TIMP-1 monoclonal antibody VT7 (Sørensen et al, J. Hist. Cytochem. 2006). A combined marker (2T) for anthracycline sensitivity was constructed as follows: 2T non-responsive (TOP2A normal and TIMP-1 positive) and 2T responsive (TOP2A abnormal and/or TIMP-1 negative). Relationships between IDFS, OS and the 2T profile were analyzed using multivariate regression analysis. Results: The assessable 623 patients differed significantly (P Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 36.

Abstract #6042 Background: Randomized trials have in general demonstrated that anthracycline-based chemotherapy prolongs disease-free and overall survival as compared to CMF-based regimens. In the Danish Breast Cancer Cooperative Group (DBCG) 89D randomised trial a 21% improvement in overall survival was observed from substitution of methotrexate in the CMF combination with epirubicin. This suggests that the additional effect of anthracyclines is confined to a subset of the patients. We have previously shown that in vitro grown cancer cells devoid of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) are more sensitive towards chemotherapy than cells expressing TIMP-1 (Davidsen et al., Br J Cancer, 2005). In addition, we have recently published (Schrohl et al., Clin Cancer Res., 2006), that patients with metastatic breast cancer and high levels of TIMP-1 in their primary tumor tissues, have a significantly reduced likelihood of obtaining an objective response to chemotherapy. Purpose: The aim of the present study was to evaluate if Tissue Inhibitor of Metalloproteinses-1 (TIMP-1) tumor cell immunoreactivity could be used to identify a subset of patients who benefits from adjuvant chemotherapy. Patients and Methods: Formalin fixed paraffin embedded tissue micro arrays from 647 patients who were enrolled in the Danish Breast Cancer Cooperative Group randomized trial 89D comparing adjuvant CMF versus adjuvant CEF were analysed for tumor cell TIMP-1 immunoreactivity. The primary end-point was invasive disease free survival (IDFS). Immunohistochemistry was performed using the anti-TIMP-1 monoclonal antibody VT7 as described previously (Sørensen et al., J. Hist. Cytochem., 2006) and the slides were scored as + or – for positive immunoreactivity. Results: Tumor cell TIMP-1 immunoreactivity was found in 75% of the tumor samples. In the CEF treated patients, individuals with TIMP-1 negative tumors had a significant longer IDFS than patients with TIMP-1 positive tumors (p=0.047). The multivariate Cox regression analysis of IDFS showed that CEF was superior to CMF among patients with TIMP-1 negative tumors (HR: 0.51; 95%CI: 0.31 to 0.84, p=0.008), while no significant difference could be demonstrated among patients with TIMP-1 positive tumors (HR: 0.86; 95%CI: 0.66 to 1.11, p=0.24). However, only a non-significanct trend could be demonstrated between TIMP-1 status and CEF versus CMF (p=0.07 for interaction). Conclusion: Lack of TIMP-1 tumor cell immunoreactivity seems to predict a favourable effect of epirubicin containing adjuvant therapy in primary breast cancer. However, an independent study is awaited to validate the potential predictive value of TIMP-1 immunoreactivity. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6042.