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Clinical trials for elderly cancer patients P063 Treatment of patients with KRAS wild type advanced colorectal cancer with 5-fluorouracil (5-FU) or 5-FU plus an epidermal growth factor receptor inhibitor (cetuximab) based on a comprehensive geriatric assessment U. Wedding*, C. Messina, M. Mauer, A. Pallis, J. Harrison, H. Wildiers, M. Peeters EORTC. Palliative Care, UKJ, Jena, Germany; EORTC, Brussels; University Hospitals, Leuven; Universiteit Antwerpen, Antwerpen, Belgium

TO THE EDITOR: The recently published comments by Brauch et al regarding our current knowledge about the importance of CYP2D6 status when prescribing tamoxifen concluded that results from ongoing prospective studies in the metastatic/neoadjuvant setting will not help to close the circle on this topic. We do agree with their conclusion that published retrospective studies—so far—do not provide sufficient evidence to determine whether or not CYP2D6 testing should be performed in daily practice. However, we believe that two registered, ongoing, prospective studies in the neoadjuvant/metastatic setting (the European CYPTAMBRUT-2 study [Study to Assess Response to Tamoxifen in (cT3)/Inoperable Locally Advanced/Metastatic Estrogen Receptor–Positive Breast Cancer by the “Tamoxifen Activity Score” Based on Drug Interaction and Polymorphisms in Genes Coding for Tamoxifen Metabolising Enzymes] and the study of the Eastern Cooperative Oncology Group E3108 [Tamoxifen Citrate in Treating Patients With Metastatic or Recurrent Breast Cancer]) will provide answers that are not available from retrospective studies and which are likely to be relevant in the adjuvant setting. Although metastatic breast cancer differs in many respects from early breast cancer, in which tamoxifen helps to eradicate subclinical disseminated disease, metabolic pathways of tamoxifen for efficacy are disease-stage independent. It is unlikely that endoxifen levels matter in the adjuvant setting if they do not matter in the metastatic setting. However, if endoxifen levels do matter in metastatic disease, it does probably but not necessarily follow that this applies in the adjuvant setting. As principal investigators of the European CYPTAMBRUT-2 study, we would like to stress that this study includes only patients in the first-line metastatic/neoadjuvant setting. Patients with hormoneinsensitive or aromatase inhibitor–refractory disease were excluded from this study, as were premenopausal women. The study has so far recruited 240 of 260 patients. The CYPTAMBRUT-2 study not only addresses response to tamoxifen according to genetic variants but also takes endoxifen levels into account. One should first elucidate the relationship between endoxifen levels and tamoxifen efficacy before investigating the relationship between genetic variants and efficacy. Tamoxifen metabolization is complex; multiple enzymes are involved, and other factors affect endoxifen levels as well. Negative results from studies that have assessed the relationship between genetic variants and efficacy could be a result of the fact that variations in endoxifen levels were not related to efficacy or that the variations in endoxifen levels were not represented well by the analyzed genetic variants. Studies examining the pharmacogenomics of tamoxifen should include the measurement of all relevant metabolites of tamoxifen, as well as all genes and gene polymorphisms that are involved in the metabolism of tamoxifen; in nearly all previous retrospective studies, this has not been the case.

1078 Background: Recently we described the impact of genetic variability on severe toxicity in breast cancer patients receiving (neo-) adjuvant FEC chemotherapy (Annals of Oncology 2013, In Press). We now further assessed the impact of a wide range of patient-related factors on FEC toxicity in routine clinical setting. Methods: Patients with early breast cancer receiving (neo-)adjuvant 6 cycles FEC or sequential 3 cycles of FEC and 3 cycles D were retrospectively evaluated through electronic chart review for febrile neutropenia (primary endpoint; CTC 3.0). Age at diagnosis, body mass index, body surface area, number of cycles received, germline genetic polymorphisms, and baseline biochemical variables (white blood cell count, absolute neutrophil count, platelets, aspartate aminotransferase, alanine aminotransferase, total bilirubin and creatinine) were available for most patients (missing data

Background: The epidermal growth factor receptor belongs to the ErbB family of cell-surface receptors. Hotspot mutations within this gene occur in 27% of lung cancers and patients carrying mutation(s) likely receive more benefit from EGFR targeted therapy. We have evaluated the feasibility of multiplex PCR targeting known mutational hotspots in EGFR exon 18 till 21, followed by 454 pyrosequencing to determine the EGFR mutational status in patients with lung cancer. Methods: FFPE samples from 10 lung cancer patients were collected. Four samples were mutant and six carried the wild-type (WT) genotype. A multiplex PCR was performed in which primers had a gene specific sequence, a patient specific ‘bar code’ (MID) and Roche sequencing tags. The unique multiplex identifiers (MIDs) allow appropriate mixing of patient samples and differentiation in the sequence data. Amplicon generation was verified by fragment analysis (GeneScan). Amplicons were purified using AMPure XP beads, quantified by Quant-iT PicoGreen, pooled in equimolar ratios and diluted before emulsion PCR. Sequencing was carried out in 2 runs using Titanium Amplicon chemistry (Lib-A) on a 454 GS Junior. Two samples were analyzed in duplicate to assess reproducibility. Data were analyzed using the amplicon variant analyzer software. Results: A throughput of 52.159 and 28.769 high quality reads was achieved for the library in the performed runs. Considering the EGFR amplicons, a mean coverage of 837 reads (range 589 - 1350) was obtained. Four variants were detected by sequencing and were 100% concordant with results obtained using a StripAssay in an ISO-certified setting. The variants and frequencies detected were G719X (21,7%), p.L747-S752del (21,46%), p.H773_V774insNPH (11,14%) and p.L861Q (24,11%). In the WT samples no EGFR mutations were detected, suggesting a 100% specificity on the obtained 454 data. Additionally, variant analysis showed 2 different SNPs in exon 20 and 21 (rs1050171 and rs17290559, respectively). These are classified as the synonymous mutations Q787Q and R836R and do not have any clinical significance. The SNPs in exon 20 and 21 were detected in 67% and 17% of the WT samples, respectively. Inter-run reproducibility was established from comparison of 2 WT samples in different sequence runs. Intra-assay reproducibility was demonstrated via analysis of EGFR mutant samples in duplicate. Conclusions: Our study provides a basis for the implementation of next generation sequencing for the detection of somatic mutations in EGFR in a routine clinical setting. The used multiplex PCR and subsequent 454 sequencing allowed the detection of significant activating or resistance associated EGFR mutations in FFPE material from patients with lung cancer. We obtained 100% concordance with previously obtained results from an accredited laboratory. Citation Format: Eleni van Schooneveld, Bram De Laere, Roberto Salgado, Peter Vermeulen, Hans Wildiers, Ignace Vergote, Luc Dirix, Steven Van Laere. Determination of the EGFR mutational status on FFPE material from patients with lung cancer using Multiplex PCR followed by sequencing on a compatible 454 sequencing platform. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4145. doi:10.1158/1538-7445.AM2013-4145

Truin et al. recently reported in Annals of Oncology on the effect of adjuvant chemotherapy in postmenopausal women (aged 50–75 years) with invasive lobular (ILC) versus ductal (IDC) breast cancer using a very large nationwide cohort [1]. Patients with IDC receiving combined (endocrine (ET) and chemo (CT)) therapy had better overall survival compared with those receiving ET only. Combined treatment did not improve overall survival in ILC, which led the authors to conclude that there seems to be no benefit of adjuvant chemotherapy in patients with ILC who receive endocrine therapy. We would like to provide those interested in this manuscript with some important remarks allowing us to conclude that the study from Truin should not be used as a proof to omit adjuvant chemotherapy in ILC

Background: Decisions about systemic treatment in women with metastatic breast cancer are currently based on the presence of estrogen receptors (ER), progesterone receptors (PR) or Human Epidermal growth factor Receptor 2 (HER2 receptors) in the primary tumor. Recently, several studies have reported significant discordances in ER, PR and HER2 status between the primary tumor and metastatic lesions and this may vary by metastatic site. Prognostic implications remain unclear although alterations in ER, PR and/or HER2 can influence metastatic management. This study represents one of the largest studies evaluating how frequent receptor discordances occur in liver metastasis, whether this alters therapeutic options and impacts prognosis. Patients and methods: 246 breast cancer patients with histological confirmed liver metastasis were analyzed in this retrospective study. Immunohistochemistry (IHC) and/or FISH were used to determine ER, PR and HER2 receptor status. We excluded patients when comparison between receptors of primary tumor and metastasis was impossible due to missing data (n = 85), when liver metastasis did not originate from breast cancer (n = 36) and when pathology was obtained from autopsy specimens (n = 38). Results: 87 patients had matched tissue samples of primary tumor and liver metastasis with possible comparison of at least one of the receptors. Table 1 summarizes changes in ER, PR, HER2 between primary and metastatic lesion. Discordance in receptor status was associated with shorter time to death (63.3 months) compared to the concordant group (75.5 months). Conclusions: A significant proportion of ER and PR show discordance between primary tumor and liver metastasis. However we could not establish the same level of discordance for the HER2 receptors as in other studies. In general, only about 1 in 5 patients gained new (endocrine or targeted) therapeutic options. Tissue confirmation remains important to evaluate whether metastatic disease has become endocrine insensitive (in approximately 1 in 5 patients), avoiding unnecessary delay in chemotherapy. Discordance in receptors may be associated with inferior prognosis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-05.

of multiple chronic diseases, a decline in functional ability and cognitive functioning, and social problems. The importance of dynamic interdisciplinary collaboration between oncology specialists and geriatricians, and the incorporation of a geriatric assessment to evaluate the health status of elderly patients and patient/familyoriented approach into geriatric oncology practice have been well established. In particular, oncology nursing specialists are at the frontiers of the interdisciplinary geriatric oncology. However, there remains limited empirical evidence to inform the treatment decision and clinical care of elderly patient with cancer, and hence considerable variability in management of elderly patients with cancer could exist. Moving forward, the combination of geriatric, gerontology and oncology nursing science is critical to meet the ever-increasing population of elderly and increased incidence of cancer among the elderly. This paper provides an overview of the state of the art of the research in geriatric oncology nursing, evaluates the need for sub-specialised care, and discusses specific research agenda for geriatric oncology assessment and nursing care.

Olivier Brouckaert, Hans Wildiers, Giuseppe Floris, Patrick NevenMultidisciplinary Breast Centre, UZ Leuven, Leuven, BelgiumAbstract: Triple negative breast cancer (TNBC) is a heterogeneous disease comprehending different orphan breast cancers simply defined by the absence of ER/PR/HER-2. Approximately 15%–20% of all breast cancers belong to this phenotype that has distinct risk factors, distinct molecular features, and a particular clinical presentation and outcome. All these features will be discussed in this review. The risk of developing TNBC varies with age, race, genetics, breastfeeding patterns, and parity. Some TNBC are very chemo-sensitive and the majority of patients confronted with and treated for TNBC will never relapse. Some (histological) subgroups of TNBC may have good prognosis even in the absence of chemotherapy. Distinct molecular subgroups within TNBC have been defined now as well. In case metastatic relapse occurs, this is usually within 5 years following surgery, and survival following metastatic relapse is shorter compared to other breast cancer subtypes; treatment options are few and responses lack durability. Novel drug targets and new biomarkers are needed to improve breast cancer care for patients presenting with TNBC. Further molecular/biological unraveling of TNBC is needed.Keywords: breast cancer, triple negative, review

1020 Background: We assessed the impact of single nucleotide polymorphisms (SNP) of potential genes of interest in germline DNA on severe adverse events in breast cancer (bc) patients receiving (neo-) adjuvant FEC chemotherapy. Methods: Cases were retrospectively evaluated through electronic chart review for febrile neutropenia (primary endpoint), febrile neutropenia first cycle, prolonged grade 4 or deep (

529 Background: AMG 386, an investigational peptibody, reduces tumor angiogenesis by blocking interaction of angiopoietins 1 and 2 with the Tie2 receptor. This interim analysis evaluates the tolerability and efficacy of AMG 386 + P/T or C/L in HER2+ MBC. Methods: In part 1, pts in cohorts A1 and A3 (no prior 1st-line MBC T or L ) received AMG 386 IV QW plus P 80 mg/m2 IV QW and T 8 mg/kg loading dose, then 6 mg/kg Q3W; pts in cohorts B1 and B3 (history of failed 1st-line MBC T treatment; no prior L or C) received AMG 386 IV QW plus C 1000 mg/m2 PO Q12 hrs, days 1-14 Q21D and L 1250 mg PO QD. A1 and B1 received AMG 386 at 10 mg/kg; A3 and B3 received AMG 386 at 30 mg/kg. In part 2, cohorts were expanded to n = 20 if ≤ 1 of 6 or ≤ 2 of 9 pts had dose-limiting toxicities (DLTs). Primary endpoints were adverse events (AEs) and DLTs; secondary endpoints included efficacy and pharmacokinetics (PK). Interim results from A1, A3, and B1 will be presented. Results: 46 pts were enrolled at interim analysis; all received ≥ 1 dose of study treatment (A1, A3, B1; n = 20, 6, 20). The median follow-up for A1, A3, and B1 was 39.6, 22.7, and 31.3 wks. Across cohorts, there was 1 DLT in A1. AEs > 50% were peripheral edema, diarrhea, fatigue and alopecia in A1 and A3 combined, and diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome (PPES), and peripheral edema in B1. AEs grade ≥3 occurring in > 2 pts were peripheral neuropathy, peripheral sensory neuropathy, dyspnea (n = 5, 4, 3, respectively, in A1 and A3 combined); PPES, diarrhea, and neutropenia (n = 6, 5, 3, respectively, in B1). Objective response rates were 80% in A1, 50% in A3, and 50% in B1. Median (95% CI) progression-free survival was 14.5 mo (6.8-20.5) in A1 and 10.1 mo (3.7-14.7) in B1. Median duration of response (DOR) was 12.6 mo (4.3-20.2) in A1 and 8.5 mo (4.1-not evaluable) in B1. PFS and DOR were not yet evaluable in A3. No changes were apparent in any PK parameters in these combinations relative to within study or historical monotherapy PK data. Conclusions: In this ongoing phase 1b study of pts with HER2+ MBC, interim results suggest that adding AMG 386 to P/T or C/L is tolerable and has antitumor activity. Updated data will be presented.

Introduction Screen detected BC has excellent outcome due to lead time and length bias, but approximately 30% of the mortality reduction through screening remains unexplained. On the other hand, not all patients with screen detected BC have excellent outcome as some will eventually relapse. Therefore, new prognostic variables in screen detected BC are needed and we here study palpability as a candidate variable. Previously, Gill et al (J Med Screen, 2006; 13:98-101), did not find an independent prognostic value for palpability within screen detected BC. Patients and methods Primary operable invasive BC treated at UZ-Leuven (01/2000 – 12/2009). Preoperative systemic therapy (n = 407), metastases at diagnosis (n = 228), male patients (n = 28) or external surgery (n = 530) were exclusion criteria. Details on treatment and pathology are described in detail elsewhere (Brouckaert et al, Breast Cancer Res Treat., 2009 May; 115 (2):349-58). We included 1610 patients with screen detected BC. Missing data for palpability were 2. Palpability was assessed preoperatively by the treating physician. Multivariable Cox proportional hazard models were used adjusting for age, size, grade, nodal status, ER, PR and HER2 receptor status and adjuvant therapy. The proportional hazard assumption for the Cox model was evaluated by including time-dependent covariates in the models, which were included when significant. Results Median follow-up is 6.1 years. Most screen detected BC are grade 1 or 2 (72%), ER (90%) positive, PR (79%) positive and 52% are palpable. Palpability (Hazard ratio (HR) 2,73 95% CI 1,26-5,92 (p = 0,0107)) is an independent prognostic variable for distant metastasis free survival together with tumor size (HR 1,01 95% CI 1,00-1,03 (p = 0,0411)) and total number of positive lymph nodes (HR 1,11 95% CI 1,06-1,16 (p Conclusion Palpability is an independent prognostic variable in screen detected BC. Disclosure All authors have declared no conflicts of interest.

Background In histological grade 2 BC molecular classification is of high value (JNCI 2006; 98:262), but clinical, pathological and immunohistochemical variables may be useful as well. We here assess the prognostic value of ‘mode of detection’ and ‘palpability’ in grade 2 BC. Patients and methods The disease free interval in all primary operable grade 2 BC from UZ Leuven (01/2000 – 05/2005) was studied. Patients with missing variables (n = 17) were excluded. Univariable and multivariable proportional hazards Cox regression using the Firth's penalization method to reduce bias in the parameter estimates were used. The assessed prognostic variables were age at diagnosis, tumor size, nodal status, BC subtype, method of detection, lobular versus other histology, systemic adjuvant therapy, nuclear grade, architectural grade, mitotic count. Estimated hazard rates (HR) are presented (only for significant variables, see table). Results 1010 patients were included. Median follow-up: 7 years 10 months. 144 events (14.3%) were observed: 52 local and 92 metastatic. In univariable analysis and compared with palpable non-screen detected BC, HR for relapse was 0.34 (95% CI 0.17-0.62) for screen detected not palpable and 0.75 (95% CI 0.49-1.12) for screen detected palpable BC. The beneficial univariable effect of ‘screen detected not palpable’ remained in the multivariable analysis, together with significant prognostic value for lymph node status and BC subtype (see Table 1 ). Table 1 . Multivariable proportional hazards Cox regression Variable HR (95% CI) Positive lymph nodes 0 Reference 1 1.11 (0.63,1.86) 2-4 1.66 (0.97,2.75) >4 3.32 (1.83, 5.85) * NNP vs other 5.63 (1.90, 14.2) Screen and Palpable Non screen - Palpable Reference Screen – Not palpable 0.38 (0.19, 0.70) Screen - Palpable 0.87 (0.56, 1.33) * ER-negative, PgR-negative, HER-2 positive Conclusion Screen-detected not-palpable BCs were found to be independently associated with a better disease free interval among women with a primary operable grade 2 invasive BC. Method of detection should be taken into account when estimating prognosis in early BC. Disclosure All authors have declared no conflicts of interest.

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6×10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8×10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2×10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8×10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8×10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3×10(-7), p(heterogeneity) = 5.1×10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours. ispartof: PLoS One vol:7 issue:8 ispartof: location:United States status: published

Background: GDC-0941 is a potent and selective oral pan-inhibitor of class I PI3K isoforms that demonstrates single-agent activity in xenograft models1,2,3. Increased phosphorylation of AKT has been observed in breast cancer (BC) cell lines treated with paclitaxel in vitro, suggesting dependence on the PI3K pathway for survival in response to chemotherapy treatment. GDC-0941 increases the antitumor activity of taxanes, associated with increased apoptotic cell death, in multiple BC xenograft models2. Material and Methods: Patients (pts) with HER2−negative locally recurrent or metastatic BC (MBC) that received no more than 2 prior anti-cancer therapies for MBC (prior paclitaxel and/or bevacizumab permitted) were enrolled in a Phase Ib study (GDC4629g) of paclitaxel and GDC-0941 with and without bevacizumab using a 3+3 dose escalation design to evaluate the safety, tolerability, and PK and determine the MTD of the combination. Paclitaxel was given at 90 mg/m2 on Days 1, 8 and 15 and bevacizumab, if applicable, at 10 mg/kg on Days 1 and 15 every 28 days. Two dosing schedules of GDC-0941 were examined: GDC-0941 given once-daily on Days 1–21 (“21+7” schedule) or given for 5 consecutive days followed by a 2-day drug holiday (“5+2” schedule, implemented to potentially to improve the efficacy and safety of the combination treatment). Results: We report data from 5 cohorts (25 pts). Sixteen of the 25 pts (64%) are hormone-receptor positive and 12 of 25 patients (48%) received prior treatment with a taxane, (all but one in the neo-adjuvant or adjuvant setting) and only one patient received prior treatment with bevacizumab. Pts in Cohort 1 received GDC-0941 60 mg given 21+7 with paclitaxel in Cycle 1; they were allowed to receive bevacizumab starting in Cycle 2. One DLT of Grade 3 subclavian vein thrombosis (in a pt with an indwelling catheter) was observed at this dose level. The cohort was expanded without any additional DLTs. In Cohorts 2 and 3, GDC-0941 was given 21+7 at 60 mg and 100 mg, respectively, with paclitaxel and bevacizumab starting in Cycle 1. In Cohort 4, GDC-0941 was given 5+2 at 165 mg with paclitaxel only. Cohort 5, with 250 mg GDC-0941 given 5+2 with paclitaxel only, is currently under evaluation. The most common drug-related AEs in 22 treated patients are in Table 1. Preliminary PK for GDC-0941, paclitaxel and 6-hydroxypaclitaxel were similar to historical profiles from previous studies of these molecules. One CR and 9 PRs (ORR 46%) have been observed to date. Conclusions: GDC-0941 given 5+2 at doses up to 165 mg QD in combination with paclitaxel is well tolerated and dose escalation continues with encouraging clinical activity. Updated safety, PK and efficacy data will be presented. 1Junttila et al, Cancer Cell 2009 2Yao et al., CCR 2009 3O'Brien et al., CCR 2010 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-04.

ErbB4 function in breast cancer is controversial and influenced by alternative splicing of the ERBB4 gene. Here we evaluated the cleavable ErbB4 JM-a isoform as a potential drug target and biomarker. Matched serum and tissue samples from a series of 243 breast cancer patients were analyzed for ErbB4 cleavage products by ELISA and immunohistochemistry. Elevated serum ectodomain level (≥40 ng/mL) was present in 21% of the patients and significantly associated with the premenopausal status at diagnosis (P = 0.04). Consistent with the in vivo data, estradiol enhanced ErbB4 shedding and TACE activity in vitro. Selective targeting of ErbB4 JM-a by mAb 1479 inhibited ErbB4 cleavage and reduced tumor formation in a mouse xenograft model. The 3.4 Å X-ray crystal structure of the sErbB4:1479Fab complex localized the binding site of mAb 1479 on ErbB4 to a region on subdomain IV encompassing JM-a-specific residues. These data demonstrate that ErbB4 cleavage can be specifically targeted in vivo, and introduce serum ErbB4 ectodomain concentration as a biomarker for monitoring the activity of compounds that target ErbB4 cleavage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B187.

544 Background: AMG 386 is an investigational peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction between the Tie2 receptor and angiopoietin-1 and -2. We assessed t...

TPS140 Background: Tamoxifen is widely used to treat hormone receptor positive breast cancers, in the (neo-)adjuvant setting as well as in the metastatic setting. Even though tamoxifen saved many l...

1018 Background: Triple negative breast cancer (TNBC) shares molecular characteristics with BRCA1-/- breast cancer (BC). Preclinical and clinical data show that BRCA1-/- BC and TNBC are sensitive to inhibition of PARP1, an enzyme necessary for DNA repair and other critical cell functions. This phase 1 study evaluated the tolerability of olaparib, a potent PARP1 inhibitor, combined with weekly paclitaxel in patients with metastatic TNBC. This trial served as a safety evaluation to be followed by a phase II trial after tolerability was determined. Methods: Eligible patients (pts) had ≤ 1 prior cytotoxic regimens for ER-, PR-, and HER2- metastatic BC. Pts were treated with olaparib 200mg capsules PO BID continuously combined with paclitaxel 90mg/m2 IV weekly for 3 of 4 weeks. At this dose, a significant number of pts had delays due to neutropenia, thus a second cohort of 10 pts was enrolled with an amendment to the protocol to allow for GCSF (300 μ g SC days 3-5) as secondary prophylaxis following weekly pac...

559 Background: For patients (pts) with HER2+ BC, concurrent AC-H results in unacceptable cardiotoxicity rates. Substituting PLD for A in an adjuvant regimen may minimize cardiotoxic risk and permit earlier integration of adjuvant H. Methods: Inthis randomized phase II trial, pts with resected lymph node+ or high-risk, node-negative HER2+ BC were stratified by age and randomized (1:2) to: Arm A: AC (60/600 mg/m2 q21d × 4) followed by T 80 mg/m2 + H 2 mg/kg qwk × 12 or Arm B: PLD 35 mg/m2 + C 600 mg/m2 q21d × 4 + H 2 mg/kg/wk × 12, followed by T 80 mg/m2 + H 2 mg/kg qwk × 12. Subsequent H for a total of 1y was given as per institutional standards. Primary objective was incidence of level 1 (cardiac death or severe heart failure with left ventricular ejection fraction [LVEF] drop > 10% to 10% to < 50%) cardiac event rates during the 8 cycles of chemotherapy (CT). This analysis reports cardiotoxicity for the entire patient population comple...

Background: For patients with HER2+ breast cancer AC + H results in unacceptable cardiotoxicity requiring sequential administration. Substituting pegylated liposomal doxorubicin (PLD) for doxorubicin in an adjuvant regimen may minimize the risk of cardiotoxicity and permit earlier integration of adjuvant H. Methods: In this multinational, open-label, parallel group trial, women ≥18 y with resected LN+, or high-risk LN- HER2+ breast cancer, were stratified by age (10% to 10% to Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2085.

Background: Invalidating hot flushes and night sweats leading to sleep dysfunction and poor quality of life are difficult to treat, especially in postmenopausal breast cancer patients likely to take an anti-estrogen. Lipov et al. (Lancet Oncology 2008; 9: 523-32) recently reported on the therapeutic value of the ganglion stellatum block (GSB) in 13 patients. We here report results from a pilot and prospectively planned study using the GSB in symptomatic breast cancer patients.Methods and Patients: Both studies were approved by our ethical committee and included postmenopausal women with severe hot flushes and/or night sweats and no contra-indication for GSB. Patients had to sign a consent form after information and were recruited from the follow-up breast cancer clinic. Hot flushes were recorded in a daily diary by use of the hot-flash score (Lipov et al.) and night awakenings by use of the Pittsburgh Sleep Quality Index. Improvement was estimated by the patient from 0-100 %. The pilot cohort compared both instruments between baseline and after 1 month whereas the prospective study compared baseline, weeks 1, 12 & 24 following the GSB. Patients were treated as out-patients in the pain clinic with a right side GSB at the anterolateral aspect of C6 vertebra under fluoroscopy by an experienced anesthetist injecting 10 cc Chirocaïne. A contralateral block was placed when no satisfactory result.Results: The pilot study included 9 patients and as of today, 18 of 25 patients are included in the prospective study. The temporary Horner syndrome confirmed the GSB in all. In the pilot study, 5/9 patients had the GSB unilateral and 4/9 bilateral. Three of 9 patients had no improvement in either endpoint while 6/9 reported an improvement in severity of hot flushes and in quality of sleep. Two patients had a complete disappearance of the hot flushes and perfect sleep quality following a unilateral GSB. Three patients with contralateral GSB experienced an 80%, 70% and 50% improvement. Another patient with GSB unilateral experienced improvement by 20% in both instruments. We report results of 6 patients in the prospective study, 3 required a contralateral GSB. Their mean baseline hot flash score was 2.5 down to 2.2 after one week of GSB. Mean sleep hours improved from 6 to 7.25 hours per night even at week 1 after the GSB. One reported a hot flash score of 2.5/1.6/1.5/1.9 respectively mentioned follow up period. Because of rising hot flash score she asked for a third GSB after 24 weeks.Conclusion: This pilot and prospectively planned study to test efficacy of GSB on hot flushes and/or night sweats confirmed that breast cancer patients suffering from invalidating symptoms may benefit with no short term harm. Further results of the patients in both studies will be presented during the meeting. This will also answer the question whether long term efficacy remains. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 809.

Background:Oral aromatase inhibitors (AI) and to a lesser extend tamoxifen can promote recovery of ovarian function in postmenopausal breast cancer patients. Biochemical monitoring of ovarian function is important as folliculogenesis may lead to pregnancy, vaginal bleeding and loss of efficacy of the oral AI. Biochemical monitoring of oestradiol in exemestane users is problematic because exemestane metabolites cross react in most immunoassays for oestradiol. Following our finding of luteal phase progesterone levels in serum of some postmenopausal women with vaginal bleeding on exemestane, we assessed potential cross reactivity between exemestane and its 4-OH metabolite in the Roche Elecsys® progesterone assay. We also studied the frequency of such progesterone activity in serum from consecutive exemestane users and correlated values with FSH.Methods:Progesterone concentrations were measured with the Elecsys® assay in blanco serum, blanco serum with pure exemestane and blanco serum with the pure 17-OH-exemestane metabolite. Several concentrations of the purifided 17-OH-exemestane metabolite in DSMO solvent were then prepared using the Elecsys Diluent MultiAssay and progesterone concentration was measured in these samples using the Elecsys® assay. Cross sectional blood samples from 94 exemestane users were measured for progesterone activity with this assay and also for FSH using the Roche Modular E170® (F. Hoffmann-La Roche Ltd, Basel, Switserland).Results:Using this progesterone assay, 41% of exemestane users had luteal phase progesterone levels (>1.7 ng/mL). There is cross reactivity with exemestane but more importantly with the 17-OH metabolite (table). The level of progesterone and cross reactivity for 2 known concentrations of the 17-OH-metabolite are also shown in this table. There is a correlation between progesterone picked up by the Elecsys® assay and FSH which increased with progesterone activity.Elecsys® assay RocheProgesterone (ng/mL)Blanco serum0.030Blanco serum + exemestane0.313Blanco serum + 17-OH-exemestane0.781Blanco serum + 2500 ng-ML 17-OH-exemestane16.20.65 %*Blanco serum + 5000 ng ng/mL 17-OH-exemestane32.50.65%/*(*): percentage of cross reactivityConclusion:Progesterone levels in exemestane users measured with the Elecsys® assay from Roche were often overestimated due to cross reactivity with exemestane and its main metabolite. This progesterone assay can not be used to define menopause or distinguish postmenopausal from menstrual bleeding in exemestane users. Higher FSH levels with higher progesterone activity in this assay suggest a link between circulating exemestane/metabolites and the quantitative downregulation of postmenopausal estrogens by this AI, but serial rather than cross sectional measurements are required to confirm this.We acknowledge Pfizer for providing us with pure exemestane and 17-OH-metabolite. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5147.

9630 Background: The bisphosphonate (BP) ZOL is frequently used to prevent skeletal-related events (SRE) in cancer pts. However, data are limited on its use beyond 2 years. LOTUZ is among the first studies to examine Rx and outcomes in pts with ZOL Rx for >2y. We report 6-month results. Methods: Prospective (18m), multicenter (50), pharmacoepidemiologic study. Baseline (0m) and 6m data available on 205 pts (of 298 enrolled), all free from osteonecrosis of the jaw (ONJ) at 0m. Prior to ZOL Rx, 27.8% had non-ZOL BP Rx. Mean pre-enrollment BP duration was 42 mo (23–145) with 38 mo (23–80) for ZOL. Results: Mean age: 64 y (38–88); M/F: 29/71%; 67.8% with MBD vs 32.2% MM. 89.3% continued ZOL RX 0–6m; 90% with dose 4mg. From 0–6m, 10 pts (4.8%) developed ONJ (4 with MM, 6 with MBD): 5 mild, 3 moderate, 2 severe (median BP duration: 38.4, 46.5, and 34.8 months, respectively). Five pts with ONJ continued on ZOL RX 0–6m (3 mild, 2 moderate). 4/10 pts with ONJ had baseline dental conditions or procedures, 8/10 at 6m (only 1/10 at neither). SREs and pain levels remained constant 0–6m compared to 6m prior to baseline (see Table ). Conclusions: Beyond 2y, 90% of pts were continued on ZOL. SREs did not increase, but ONJ was diagnosed in 10/205 pts 0–6m, of which 5 were on ZOL RX beyond 24m. Long-term data are needed to better understand the risk/benefit of long-term ZOL Rx. [Table: see text] [Table: see text]

3565 Background: SUN and SOR are multi-targeted tyrosine kinase inhibitors (TKIs) inhibiting several kinases (VEGFR- 1,2; c-kit; PDGFR-α,β; flt-3; RET). SUN is approved for treatment of imatinib-resistant gastrointestinal stromal tumors (GIST) and metastatic renal cell carcinoma (RCC), SOR is used for RCC and hepatocellular carcinoma. We observed in some pts with fatigue under TKI treatment low testosterone (T) levels and started assessing the incidence and severity of gonadal dysfunction prospectively in male pts receiving these TKIs. Methods: Gonadal status (serum total testosterone (TT), free testosterone (FT), sex-hormone binding globulin (SHBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were evaluated in pts with RCC or GIST under SUN or SOR. SUN was given at a daily dose of 50 mg p.o. 4 weeks on, 2 weeks off, SOR at a daily oral dose of 800 mg. Results: We identified 27 pts (median age 63, range: 27–77), for which data on gonadal function were available, 23 RCC (85 %), 4 GIST (15%), with 22 (85.5%) receiving SUN and 5 (18.5%) SOR. Median treatment duration was 48 (2–202) weeks, 13 (48%) underwent dose reductions, in 4 (15%) pts due to grade 3 fatigue. All pts had at least once during TKI treatment T levels lower than normal (TT < 300 ng/dL and/or FT < 5 ng/dL), 17 (63%) had a low T with normal LH/FSH, 4 (15%) a low T with an elevated LH/FSH and 6 (22%) a low T and elevated FSH, but normal LH. The median TT level in the whole group was 194 ng/dL (21–477, normal range: 300–1,000 ng/dL), the median FT level in the whole group was 4.01 (0.45–9.07, normal range: 5–20 ng/dL). In the SUN cohort the median levels for TT and FT were slightly lower on day 28 in comparison to day 1 (184.5 vs 206 ng/dL for TT and 3.935 vs 4.225 ng/dl for FT). Pts with information available on testosterone at baseline (n = 8) tended to have slightly diminished baseline T levels (median: 222.5 [61–319] ng/dL), but 50% of these pts had been treated with other TKIs before. Two pts with grade 3 fatigue under SUN had very low T levels shortly after starting SUN (21 and 28 ng/dL, respectively). Conclusions: We observed a high incidence of hypogonadism in male RCC and GIST pts under treatment with SUN or SOR. Hypogonadism may likely contribute to the fatigue associated with these agents. [Table: see text]

Abstract #5115 Background: Addition of X to T significantly improves RR, TTP and OS vs T alone in metastatic breast cancer (MBC). Addition of X to first-line TH in HER2-positive MBC significantly improves PFS and TTP. X and T are synergistic with H in HER2-positive tumors. We present final efficacy data of TX ±H in LABC. Materials and methods: Pts with newly diagnosed invasive stage III inoperable BC (cT4 and/or cN2–3) received X (900 mg/m2 orally bid d1–14) + T (36 mg/m2 i.v. d1&8) q3w x6, followed by surgery and radiotherapy. Pts with HER2-positive tumors (IHC 3+ or FISH+) also received H (8 mg/kg d1 of the first cycle and 6 mg/kg d1 of subsequent cycles). Safety was evaluated after each cycle, clinical response after 3 and 6 cycles, and pathological complete response (pCR) postoperatively (pCR = no residual invasive tumor in breast and axilla). Results: Between Dec 2003 and Dec 2007, 43 pts with HER2-positive LABC were treated with TXH and 52 with HER2-negative LABC received TX. pCR rate was 21/43 (49%) with TXH and 10/52 (19%) with TX. In the TXH cohort, pts without pCR included 1 pt with disease progression and 2 pts who refused mastectomy after chemotherapy. At the meeting, full data on the whole group, including baseline characteristics and toxicity, will be presented. Conclusions: TX±H, a neoadjuvant regimen without anthracyclines, is an effective regimen in the neoadjuvant setting. pCR rate is lower in the TX arm (19%) than in the TXH arm (49%). This shows the important contribution of H in achieving pCR, although the different biology of HER2-positive tumors might also account for differences in efficacy. TX is an attractive regimen to combine with H since it is a highly effective regimen and less cardiotoxic in contrast with anthracycline based regimens. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5115.

20597 Background: There is a trend towards long-term Rx with ZOL. The LOTUZ study is among the first to examine ZOL Rx treatment patterns, effectiveness, and safety beyond 2 years. Reported are bas...

16145 Background: Sorafenib is an oral multi-target tyrosine kinase inhibitor (TKI) approved for the treatment of metastatic RCC. A high incidence of thyroid dysfunction has been observed with sunitinib, another TKI with overlapping mechanism of action. We evaluated prospectively the incidence and severity of thyroid function abnormalities in pts with metastatic RCC treated with sorafenib. Methods: A total of 46 patients received sorafenib for metastatic RCC and 38 patients were eligible for our single-centre prospective observational study. Sorafenib was administered continuously at a dose of 400 mg orally twice daily. Thyroid function (TSH, free thyroxine index) was assessed at baseline and on day 1 of each treatment cycle. Results: Of the 23 patients with normal baseline thyroid function, 7 patients (30%) developed at least one elevated serum TSH and one patient (5%) developed low TSH without requiring therapy. Fifteen patients (65%) did not develop any TFT abnormality. In the group of 15 pts with thyr...

Background: A growing and diverse aging population, recent advances in research on aging and cancer, and the fact that a disproportional burden of cancer still occurs in people aged 65 years and older have generated great interest in delivering better cancer care for older adults. Cancer and its treatment precipitate classic geriatric syndromes such as falls, malnutrition, delirium, and urinary incontinence. Comprehensive Geriatric Assessment (CGA) offers a model of integrating medical care with social support services and is characterized by a multidimensional assessment of the general health where functional, cognitive and psychosocial parameters are evaluated by validated tools. However, the drawbacks of CGA include a time-consuming realization for busy clinicians, the lack of trained staff even in large academic hospitals and no financial rewards by most health insurance systems. For these reasons, CGA is rarely applied in clinical practice. There is increasing interest in the use of shorter screening tools and their validation is eagerly awaited. The aim of this study is to examine the sensitivity and specificity of the 2-item Geriatric Depression Scale (GDS) and the Watson clock test compared to the more routinely used 15-item GDS and the Mini Mental State Examination (MMSE) in the detection of depression and cognitive decline in elderly cancer patients. Methods: The study was conducted between 11-2003 and 3-2005 in the University Hospitals of Leuven, Belgium. It was designed as a prospective descriptive cohort study. One hundred five patients with various cancers (breast tumour 38.1%, gastrointestinal tumour 28.6%, various 33.3%) were included with a mean age of 76.4 years (SD= 5.18). All the patients were about to start a new treatment with chemotherapy or elective cancer surgery. The patient underwent a brief interview by 3 dedicated nurses using the 2-item GDS, the 15-item GDS, the Watson clock test and the MMSE. The Watson clock test and MMSE data were missing in 3 patients. Results: Table 1: The 2-item GDS compared to the 15-item GDS as gold standard in n = 105 patients

8537 Background: Surgery is the treatment of choice for solid cancers. Frequent functional impairment/comorbidities in the elderly enhances the risk of treatment related complications. Inability to forecast short term outcomes after cancer surgery in elderly affects clinical practice, denying optimal treatment. No validated instrument is available to help make informed decision; a compilation of validated questionnaires (PACE) is established to preoperatively inform on the health condition of elderly cancer pts. This international multicentre study investigates how components of PACE preoperatively assessed are associated with postoperative outcomes. Methods: A prospective series of consenting elderly cancer pts (≥70 yrs) receiving elective surgery (moderate-major+) were recruited from 8 hospitals (UK, Netherlands, Italy, Japan, Belgium) (07/2003–12/2005) and assessed using PACE (Comorbidities, IADL, ADL, GDS, BFI, PS, MMS, ASA). 30day morbidity, hospital stay and mortality were recorded. Results: 448 pts [breast (48%), GI (30%), GU (16%), miscellaneous (6%)] were recruited and followed postoperatively. Observed morbidity was 36% (161 pts), mortality 4% (16 pts) and median hospital stay was 5 days (range 2 -10). All components of PACE but ASA were associated with morbidity (p80% had a longer hospital stay. Conclusions: BFI, PS and IADL appear to be the most relevant prognosticators of short term surgical outcomes. A holistic appraisal of elderly pts undergoing surgery is warmly recommended when consenting the patient and during the decision making process. No significant financial relationships to disclose.

3092 Background: Sunitinib is a multi-target tyrosine kinase inhibitor with anti-angiogenic and anti-proliferative activity mediated by signal blockade of VEGFR1/2, KIT, PDGFRα/β, and FLT-3. Phase II/III trials have demonstrated efficacy of the oral agent in Imatinib-resistant GIST and advanced renal cell cancer (RCC). We observed several cases of thyroid dysfunction in GIST during treatment with sunitinib suggesting that the drug may be associated with hypothyroidism. We therefore assessed the incidence and severity of thyroid dysfunction in cancer patients treated with sunitinib. Methods: Thyroid function (serum TSH, T3 and free thyroxin index) and thyroid antibodies (anti-TPO, -Tg and TSH-R-Ab) were evaluated retrospectively in a cohort of patients with GIST in a Phase III trial and in an expanded access program (1st part of the investigation) and in a prospective cohort of RCC and GIST patients treated in the framework of expanded access programs (2nd part). Sunitinib was given at a daily oral dose of 50 mg 4 weeks on, 2 weeks off. Thyroid parameters were assessed on days 1 and 28 of each treatment cycle in the prospective cohort. We report here the first TSH results, the full data set will be available at ASCO. Results: We identified a total of 46 patients who received sunitinib, and 33 of these patients were evaluable for thyroid function. 14 patients were analyzed retrospectively (all GIST), 19 patients prospectively (8 GIST, 11 RCC). 7 of these 19 patients (37%) showed an elevated TSH (>5 mIU/L) during treatment. In the retrospective analysis of 14 patients with a median treatment duration of 44 weeks, 8 patients (57%) had developed hypothyroidism. All patients with GIST in randomized Phase III trial remaining under active treatment with sunitinib for 58–80 weeks show an increased TSH (up to 83 mIU/L) during the course of treatment, requiring hormone substitution. In a cohort of 11 patients with RCC, after 6 weeks of treatment, 3 patients already have an increased TSH. Conclusions: Sunitinib is associated with a high incidence of thyroid dysfunction which requires further study. The mechanism by which Sunitinib induces thyroid dysfunction is yet unclear. No significant financial relationships to disclose.

9680 Background: Matrix metalloproteinases (MMPs) belong to a family of enzymes involved in degradation of the extracellular matrix, a key event in tumor progression, invasion and metastasis. Upreg...

This study investigated volumetric brain changes and cognitive performance in premenopausal and postmenopausal patients treated for early-stage breast cancer. Participants underwent elaborate neurocognitive assessments (neuropsychological testing, cognitive failure questionnaire, and high-resolution T1-weighted structural MRI) before and after chemotherapy. Volumetric brain changes were estimated, using longitudinal deformation-based morphometry, and correlated with cognitive changes. In total, 180 women participated in this study, of whom 72 patients with breast cancer had received adjuvant chemotherapy (C+), 49 patients did not receive chemotherapy (C-), and 59 healthy controls (HC). The population was categorized into two age groups: A young group who were premenopausal and younger than 52 years at baseline (n = 55C+/32C-/41HC), and an older group who were postmenopausal and older than 60 years (n = 17C+/17C-/18HC). Cognitive impairment occurred after chemotherapy in both young and older patients, although older patients showed more decline in processing speed (Trail making test b). White matter volume expansion was observed after chemotherapy, only significantly present in the younger subgroup of patients. In patients not treated with chemotherapy, diffuse gray and white matter volume reduction was observed. Less white matter expansion concurred with more cognitive decline (r > .349, p

9035 Background: The aim of this prospective study was to examine how age and standard clinical approach with and without CGA results determine treatment decisions in older cancer patients (pts). Methods: This study,conducted in 2 Belgian university hospitals, included pts ≥ 70 years with a malignant tumor (breast, colorectal, ovarian, lung, prostate and hematological) if a new cancer therapy was considered. All pts underwent a uniform CGA. Results were communicated to the treating physician. After the treatment decision, an interview with the treating physician was performed, using a predefined questionnaire: 1/ What would be your oncological treatment proposal in case the pt was 55y without other comorbidity? 2/ Is this different from your treatment proposal for this pt according to age and standard clinical approach without CGA results? 3/ Is this different from your treatment proposal for this pt with CGA results? Results: From October 2009 till July 2011, 937 pts were included in the study. Median age was 76y (range 70-95) and 63.5% was female. A total of 902 (96.3%) questionnaires were completed and 56.2% of the physicians were aware of the CGA results at treatment decision. In 381 pts (42.2%; 95%CI 39.0-45.5) age and standard clinical approach led to a different treatment decision compared to younger pts without comorbidity. This influence was most prominent for chemotherapy decisions: 309 patients did not receive standard chemotherapy (reduced dose (13), less toxic regimen (163), less toxic regimen at reduced dose (5) or no chemotherapy (128)). When the physician was aware of the CGA, these results influenced their treatment in 6.7% (95%CI: 4.5-8.9), mostly concerning chemotherapy. In 8 pts CGA results encouraged the treating physician to choose a more aggressive chemotherapy regimen and in 11 pts CGA results led to a decision of palliative care. Conclusions: Based on this prospective trial, we conclude that physicians use adapted treatment regimens in older versus younger pts, only based on age and standard clinical approach. CGA results change the treatment decision in 6.7% and sometimes trigger the use of a more aggressive treatment.