Citations

Abstract Background & Aims: Most GIST harbor oncogenic KIT or PDGFRA mutations, which are in most cases heterozygous. However, most GIST co-express both wild-type KIT and PDGFRA with the mutated KIT or PDGFRA. Signaling mediated by heterodimers of the wild-type receptors contribute to GIST growth even after blocking oncogenic signaling by KIT/PDGFRA inhibitors such as imatinib. Previously we found that crenolanib (CP-868596), a PDGFRA/B tyrosine kinase inhibitor with >100-fold selectivity over other tyrosine kinases including KIT and a potent inhibitor of oncogenic PDGFRA signaling in vitro, inhibited the proliferation of KIT+PDGFRA+PDGFRB− GIST-T1 cells with a potency comparable to that of imatinib (IC50: 5.3 nM; imatinib: IC50: 3.5 nM) but had very little effect in the KITlow/−PDGFRAlow/−PDGFRB+ GIST48B cells (maximum inhibition: <50%; IC50>75 nM) and in mouse stem cells for interstitial cells of Cajal (ICC-SC), a presumed cellular source for GIST, which share a phenotype with GIST48B cells (IC50 >600 nM; Hayashi et al., Gastroenterology 2012; 142:S30). Here we investigated whether the antiproliferative effect of crenolanib was dependent on KIT expression, and studied crenolanib's effect on KIT/PDGFRA signaling and on the stability of ETV1, a transcription factor required for GIST growth and survival. Methods: Protein expression and phosphorylation were studied by Western blotting. KITlow/−PDGFRAlow/+PDGFRB+ murine ICC-SC (2xSCS2F10) were retrovirally transduced to express wild-type murine KIT. Cell proliferation was studied by methyl-tetrazolium salt assay. Results: Expression of wild-type KIT in retrovirally transduced ICC-SC dramatically reduced crenolanib's IC50 from 1157 nM to 121 nM. In GIST-T1 cells, crenolanib significantly reduced PDGFRA and KIT protein expression, inhibited PDGFRA phosphorylation (IC50: 5 nM) but had no effect on KIT phosphorylation. Crenolanib applied at 8.3 nM concentration rapidly and profoundly inhibited phosphorylation of ERK1/2 MAP kinases and reduced ETV1 protein levels by >50% in 2 h. The MEK inhibitor PD98059 (50 μM) reproduced crenolanib's effect on ETV1 protein levels with an identical time-course. The inhibitory effects of both crenolanib and PD98059 on ETV1 protein expression could be reversed with the proteasome inhibitor MG132 (10 μM) and accentuated with the protein synthesis inhibitor cycloheximide (10 μg/mL). ETV1 was undetectable in the crenolanib-resistant, KITlow/−PDGFRAlow/−PDGFRB+ GIST48B cells. Conclusions: In KIT mutant, KIT+PDGFRA+PDGFRB− GIST cells, crenolanib induced ETV1 protein degradation by suppressing PDGFRA-dependent MAPK phosphorylation. Crenolanib's antiproliferative effect in these cells may depend on KIT-induced ETV1 expression and reflect the destabilization of ETV1. Grant support: NIH DK58185. Citation Format: Yujiro Hayashi, Michael R. Bardsley, Yoshitaka Toyomasu, Takahiro Taguchi, Brian P. Rubin, Monique Carter, Abhijit Ramachandran, Tamas Ordog. Crenolanib, a highly selective platelet-derived growth factor receptor α/β (PDGFRA/B) tyrosine kinase inhibitor, destabilizes ETV1 protein in KIT-mutant gastrointestinal stromal tumor (GIST) cells. [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 1035. doi:10.1158/1538-7445.AM2013-1035

Abstract Background: Preplanned combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and North Central Cancer Treatment Group (NCCTG) (Alliance) N9831 Trial compared adjuvant chemotherapy with or without trastuzumab in women with HER2-positive breast cancer. The initial results were reported in 2005 and updated in early 2011 Methods: 4045 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The definitive analysis for OS will occur when 710 events have been reported. Results: Median time on study is 8 years. The required number of events have occurred for the definitive analysis for OS to be conducted by the end of September 2012. Updated analyses of disease free survival and related subgroups will also be presented. Supported by NCI grants U10-CA-12027, -69651, -37377, -69974, -44066, U24-CA-114732, CA25224; Breast Cancer Research Foundation; Genentech 35–03 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-5.

Abstract Background: Epidermal Growth Factor Receptor (EGFR, HER1) is known to heterodimerize with HER2 and may impact the effectiveness of trastuzumab. Historically, EGFR has been difficult to measure; thus there is no evidence regarding its effects on trastuzumab clinical therapy. Here we use a new, standardized, quantitative immunofluorescence assay and a novel EGFR antibody to evaluate the correlation between EGFR expression and clinical outcome in a cohort from the North Central Cancer Treatment Group (NCCTG, Alliance) N9831 trial. Methods: Of the 3505 women in the N9831 trial, tissue microarrays were constructed that allowed analysis of 1,444 patients randomly assigned to receive chemotherapy alone (Arm A), sequential trastuzumab after chemotherapy (Arm B) or concurrent trastuzumab with chemotherapy (Arm C). Fluorescence-based, standardized measurement of EGFR was done using the rabbit monoclonal EGFR antibody D38B1 on the AQUA platform (HistoRx). EGFR expression levels were analyzed as a continuous variable and dichotomized using recursive partitioning to define an optimal cut point. The cut point was validated on an independent retrospective cohort comprised of 130 patients with HER2-positive metastatic breast cancer who received trastuzumab. Results: EGFR assessed as a continuous variable shows an association with disease free survival (DFS) in Arm C (p = 0.002) but not in Arms A or B. Dichotomizing EGFR expression shows that high level expression is associated with worse outcome (HR = 2.2; 95% CI 1.33–3.59, p = 0.002) in arm C. Five year DFS within the low level EGFR expression group was 71%, 74% and 90% for Arms A, B and C, respectively (log-rank p-value=0.02) and within the high level EGFR expression (n = 213) group was 62%, 76% and 74% respectively (log-rank p-value 0.22). As validation, the same cut-point was used to define high EGFR expression in a retrospective metastatic breast cancer cohort. The median progression free survival difference between EGFR high group and EGFR low group was 6.1 months (p = 0.0063) and the hazard ratio of high EGFR was 1.92 (p = 0.0073). Conclusions: High expression of EGFR by the AQUA platform appears to be associated with decreased benefit from adjuvant concurrent (not sequential) trastuzumab and shorter PFS in the metastatic setting. The biological underpinning for these observations is being considered. Since there are other treatment options for HER2-driven tumors, this marker, once validated, could help select patients for alternative or additive therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-4.

Abstract Background: The utility of sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy (NAC) in patients presenting with node-positive breast cancer has not been determined. The American College of Surgeons Oncology Group (ACOSOG) Z0171 trial was designed to evaluate SLN surgery after NAC in women presenting with node positive disease. Methods: ACOSOG Z1071 enrolled women with clinical T0-4, N1-2, M0 breast cancer receiving NAC. At the time of surgery, all patients were to undergo SLN surgery followed by axillary lymph node dissection (ALND). The primary endpoint was false negative rate (FNR) in women with cN1 disease with 2 or more SLNs reviewed. Positive SLNs were defined as metastases >0.2mm on H&E. The protocol encouraged dual tracer technique. A Bayesian study design with a non-informative prior was chosen to assess whether the probability that the SLN surgery FNR is greater than 10%. Results: From July 2009 to July 2011, 756 patients were enrolled from 136 institutions. Fifteen women were ineligible and 33 withdrew. Of 708 evaluable pts (668 cN1, 40 cN2), 643 had a SLN identified and an ALND (607 cN1, with indeterminate SLN results in 2); 52 pts (48 cN1) had no SLN identified and had ALND; 11 underwent ALND only (all cN1), and 2 pts had SLN only (both cN1). In patients with SLN and ALND, the SLN identification rate was 92.5% (92.7% in cN1, 90% in cN2). SLN correctly identified nodal status in 84% of the 695 pts [258 of pathologically node negative and 327 of pathologically node positive; cN1: 83.8% (549/655), cN2: 90.0% (36/40)]. Of the 643 pts with a SLN identified there was a complete pathologic response in 40.3% (40.3 % for cN1 and 50% for cN2). Of the pts with a positive SLN, the SLN was the only site of disease in 40%. For pts with cN1 disease with 2+ SLNs identified with residual nodal disease, the SLN FNR was 12.8%. In pts with dual tracer technique the FNR was 11.1%. There were no FN results among pts with cN2 disease with 2+ SLNs reviewed. Of the 40 pts with a false negative SLN of the 528 cN1 patients with 2+ SLNs examined, the number of positive nodes at ALND was 1 (50.0%); 2 (25%); 3 (10.0%) and 4–9 (15.0%). Conclusions: NAC resulted in eradication of lymph node disease in 40% of node positive breast cancer patients. SLN surgery after NAC in node positive breast cancer pts correctly identified nodal status in 84% of all patients and was associated with a FNR of 12.8%. The FNR of SLN is higher than the prespecified study endpoint of 10%. Further analysis of factors associated with FNR such as clinical response, histological findings and axillary ultrasound findings is warranted prior to widespread use of SLN in these patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S2-1.

Abstract Background: CYP2D6 is the rate limiting enzyme responsible for the metabolic activation of tamoxifen (tam) to endoxifen. Compared to CYP2D6 poor metabolizers (PM), tam-treated CYP2D6 extensive metabolizers (EM) have higher endoxifen concentrations, more vasomotor symptoms (Goetz, MP J Clin Oncol 2005), and are more likely to discontinue tam (Rae, JM 2009. Pharmacogenomics J). Additionally, higher endoxifen concentrations are associated with a stepwise increase in tam side-effects (Lorizio, W Breast Cancer Res Treat 2012). The data regarding CYP2D6 genotype and recurrence is mixed. Venlafaxine is a weak CYP2D6 inhibitor not known to alter tam pharmacokinetics (PK) and commonly recommended for tam induced hot flashes. We conducted a multicenter pharmacological study to determine whether venlafaxine altered the PK of tam and to determine the distribution of CYP2D6 genotypes in this population Methods: Women taking tam for at least 4 weeks and for whom venlafaxine was recommended for the treatment of hot flashes were eligible. Blood samples were collected prior to and 8–16 weeks following initiation of venlafaxine for steady state tam and metabolites. Genotyping was performed for alleles associated with no (PM; *3, *4, *5,*6); reduced (intermediate, IM; *10, 17 and *41); and ultra-rapid (UM; *1×2) metabolism. Power calculations demonstrated that 17 patients with paired samples were required (two-sided alpha=0.05 t-test, 90% power) to detect a 25% change in endoxifen levels after at least 8 weeks of concurrent treatment. Results: 30 women (median age 48.5) initiated venlafaxine. CYP2D6 genotypes were within Hardy Weinberg Equilibrium (HWE). CYP2D6 UM allele frequency (6.7%) was higher while CYP2D6 *4 (13.3%) was lower than expected compared to an unselected population (0.5 and 21% respectively; Sachse Am. J. Hum. Genet. 1997), resulting in the absence of CYP2D6 PM/PM. Mean (min/max) baseline endoxifen concentrations (8.73; 1.5–20.5 ng/ml) were correlated with CYP2D6 phenotype as follows: intermediate (EM/PM, PM/IM): 6.8 (1.5–11.2); extensive (EM/EM, EM/IM): 9.4 (1.5–20.5) and ultra-rapid (UM/EM: 11.0; 7.8–14) (r2 = 0.35 p = 0.05). In patients with paired samples (n = 20), venlafaxine resulted in a 23% decrease in endoxifen (−2.06 ng/ml; 95% CI −0.69 to −3.04; p = 0.004), but not tam, NDMT, or 4HT concentrations. Following initiation of venlafaxine, CYP2D6 genotype was no longer associated with endoxifen concentrations (r2 = 0.28 p = 0.23). For women with reduced CYP2D6 metabolism [EM/PM (n = 9) or PM/IM (n = 1)], venlafaxine lowered endoxifen concentrations (−2.98 ng/ml) to a level (5.41 ng/ml) reported to be associated with a higher risk of recurrence in adjuvant tam treated patients (Madlensky, L Clin Pharmacol Ther 2011). Conclusions: In this study, women with tam-induced vasomotor symptoms requiring venlafaxine were comprised predominantly of CYP2D6 EM and UM metabolizers. Venlafaxine significantly decreased endoxifen concentrations. Although the optimal concentration of endoxifen is unknown, given prior data linking low endoxifen concentrations with recurrence, venlafaxine should be used with caution in tam treated patients. (Supported by R01CA133049) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-08.

Abstract Hepatotoxicity is associated with small molecule tyrosine kinase inhibitors (TKI) in use for the treatment of a variety of cancers. Retrospective studies have identified and confirmed that specific Class II Human Leukocyte Antigen (HLA) alleles are strongly associated with ALT elevation in women treated with the TKI lapatinib for breast cancer. This study aimed to further evaluate and validate the role of the specified HLA alleles as predictors of elevated ALT in a pre-defined analysis of a large, randomized, double-blind, placebo-controlled study of lapatinib monotherapy in early stage HER2 positive breast cancer, the TEACH study (Tykerb Evaluation After Chemotherapy, EGF105485). This prospectively defined pharmacogenetic study compared the frequency of hepatobiliary adverse events between pre-specified Major Histocompatibility Complex (MHC) genetic variants, including the HLA alleles DQA1*02:01 and DRB1*07:01. The primary focus was on elevated ALT, as well as rare cases of concurrent ALT (>3x ULN) and bilirubin (>2x ULN) elevation, which represent possible Hy's Law cases and a high risk of acute liver failure, among 1194 patients randomized to lapatinib treatment from whom pharmacogenetic data was available. This study prospectively validated prior reports of the association of the specified MHC variants with elevated ALT among women treated with lapatinib. The strongest effects were observed for carriers of the HLA alleles DQA1*02:01 and DRB1*07:01, with odds ratios of 20 (95% CI: 8–40) between cases (n = 34) and controls (n = 807–808). These two HLA alleles are highly correlated, inherited together in most individuals and are consistent with a single genetic association. The overall risk of patients having an ALT (>3xULN) elevation was 3.0% and 0.7% during treatment with lapatinib and placebo respectively. Carriers of either HLA allele had a 12% chance (positive predictive value) of having an elevated ALT (>3xULN), in contrast to a 0.9% risk (negative predictive value, 99.1%) for non-carriers of the specified HLA alleles. These associations were maintained for higher ALT elevation thresholds and for cases of concurrent ALT and TBL elevation, consistent with possible Hy's Law cases. These results strongly support the role of Class II HLA-modulated immune mechanisms in lapatinib-induced hepatotoxicity. Our results validate the large strength of association of the HLA alleles DRB1*07:01 and DQA1*02:01 with hepatotoxicity and provide the possibility of managing the risk of hepatotoxicity in women receiving lapatinib for early or late stage HER2 positive breast cancer. This association with immune mechanisms may have implications for toxicities with other TKIs in current use in cancer patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-05.

Abstract Background: Adding adjuvant trastuzumab to chemotherapy for patients (pts) with resected HER2+ breast cancer (BC) improves disease free and overall survival (Perez EA, et al. J Clin Oncol 2011). Understanding which pts are most likely to benefit from these therapies is a goal of our team. Methods: Baseline 1639 annotated tumor specimens from pts enrolled in the phase III N9831 adjuvant trastuzumab trial (NCT00005970) were processed via the >29,000 gene probe DASL technology (Illumina) to identify genomic predictors of pt outcome to Arm A chemotherapy or Arm C chemotherapy plus concurrent trastuzumab. Samples were spotted in 96 well plates, with appropriate replicates. Extensive quality control and internal validation were performed. The association of each gene with recurrence-free survival (RFS) was determined for each treatment arm separately using CoxPH models adjusted for clinical and tumor risk factors. A p < 0.0001 was used to define significance. A geneset analysis (using 408 Kegg/BioCarta genesets) was performed to determine pathways associated with RFS. Results: PRPF4B, EWSR1, BMI1, CNNM1, FOXO4, CLIP2, MCCC1, CHRM2 were found to be significantly associated with RFS for Arm A and AAK1, DAZAP2, TP53INP1, MACF1 and ADHFE1 were associated with RFS for Arm C. The most significant pathway associated with RFS in Arm A was the KEGG hypertrophic cardiomyopathy pathway and for Arm C, the BioCarta pertussis toxin-insensitive CCR5 signaling in macrophage pathway. Conclusions: We have identified 8 genes associated with RFS for pts treated with adjuvant chemotherapy, and 5 genes associated with RFS for pts treated with concurrent trastuzumab and chemotherapy in pts with HER2 early stage BC. In addition, geneset analysis identified BioCarta and Kegg pathways associated with RFS for each arm. Validation in an independent cohort is expected to be completed by the end of 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-04.

Abstract Background: Neoadjuvant aromatase inhibitor (AI) therapy would become a more acceptable alternative to chemotherapy if there was a way to identify AI-resistant cases early for triage to alternate systemic treatment. We therefore conducted a Phase 2 trial of post-menopausal patients with clinical stage 2 or 3 ER+ (Allred Score 6 to 8) breast cancer who were re-biopsied 2 to 4 weeks after initiating neoadjuvant AI therapy. If the tumor Ki67 level was > 10% (AI resistant) the patient was triaged to either chemotherapy or immediate surgery and if < 10% (AI sensitive) the patient completed 16 to 18 weeks of neoadjuvant AI treatment. Co-primary endpoints were: 1) to confirm that the pathological complete response (pCR) rate to standard NCCN chemotherapy in the AI resistant population is in the range of 20% (similar to ER− disease). This required the observation of least 4/35 pCRs; 2) whether patients were willing to accept a recommendation of no chemotherapy when the preoperative endocrine prognostic index score was zero (PEPI-0) (pStage 1 or 2A, Ki67<2.7% and ER+) since, according to the PEPI model, these patients have such a low relapse risk that chemotherapy is unlikely to be of value (Ellis, M JNCI 100:1380–8, 2008). Feasible was defined as <10% PEPI-0 cases receiving adjuvant chemotherapy. Secondary endpoints included a determination of the distribution of intrinsic subtypes in the AI sensitive and resistant groups (using a research use only assay). Results: 51 patients (21%) had 2 to 4 week Ki67>10%, of these 36 received chemotherapy per protocol (27) anthracycline (A) and taxane (T)-based, 7 T-based, 1 A-only based and 1 other (non-NCCN) regimen but only 2 patients had a pCR (5.5%). 194 patients (79%) had a Ki67 <10%, of these 176 had PEPI score information. 65 had a PEPI-0 (37%), of which 61 (94%) reported a treatment plan that did not include adjuvant chemotherapy. The AI resistant group had a significantly higher frequency of baseline high-risk intrinsic subtypes (LumB: 26, HER2-E: 2 versus LumA: 7) at baseline than the AI sensitive group (LumB: 40, HER2-E: 0 versus LumA: 66) Fishers exact test p = 7.16E−6. Additional molecular data will be presented at the meeting. Conclusion. A Ki67 value >10% at 2 to 4 weeks strongly enriches for high-risk molecular subtypes (mainly LumB) however standard neoadjuvant chemotherapy did not meet pre-assigned criteria for adequate Phase 2 activity in this group. Novel neoadjuvant approaches for AI resistant-disease defined by high on treatment Ki67 are therefore a high priority. Management of patients with excellent response to neoadjuvant endocrine therapy (PEPI-0) without adjuvant chemotherapy is feasible. The ALTERNATE trial will enroll over 2000 patients to establish a new standard of care for neoadjuvant treatment of ER+ HER2− disease based on these principles. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-01.

Abstract Introduction: The appropriate assessment of HER2 amplification status is critical to determining which patients should receive HER2-directed therapy. An alternative to FISH is D-ISH (Ventana Medical Systems Tucson, Arizona) which utilizes chromogenic HER2 and chromosome 17 probes. Both FISH and D-ISH utilize formalin-fixed, paraffin-embedded (FFPE) human breast cancer tissue specimens. D-ISH has two principle advantages over FISH: it can be visualized using light microscopy and after analysis the specimens can be archived. Methods: We tested 250 samples with FISH and with D-ISH. Fifty specimens were controls: 25 cases with no HER2 or CEP17anomaly and 25 cases with HER2 amplification. There were also 200 test subjects of 50 cases each of chromosome 17 aneusomy, HER2 deletion (HER2/CEP17 ratio <0.8), HER2 duplication (HER2/CEP17 ratio 1.3–1.8), and equivocal results (HER2/CEP17 ratios between 1.8 and 2.2). FISH (Abbott Molecular) and D-ISH analysis were performed using methods described in the appropriate clinical kit package inserts, with the following exception: Four cases with CEP17 and HER2 co-amplification were also included and for FISH analysis these cases were reflexed to the use of chromosome 17 control probe (D17S122). Results: Four samples failed testing by D-ISH. There was a 63% (155/246) concordance between FISH and D-ISH by anomaly (aneusomy, duplication, deletion, etc.) and an 83% concordance by amplification status (non-amplified, equivocal, and amplified). D-ISH detected 18 (62%) of F-ISH-amplified cases. D-ISH resulted in lower estimates of HER2/CEP17 ratios than FISH, and many cases that were equivocal by FISH were normal by D-ISH. D-ISH did not detect HER2 amplification in any of the four HER2 and CEP17 co-amplified cases. Conclusions: We observed a lower concordance rate between FISH and D-ISH than the ∼95% rate in the D-ISH package insert. This lower concordance rate is likely a result of how this study was designed: it was biased toward common chromosome 17 anomalies and difficult specimens. Such specimens comprise about 60% of our current clinical HER2 biomarker practice. D-ISH may underestimate the HER2/CEP17 ratio, or FISH may overestimate this ratio. D-ISH also does not reliably detect HER2 amplification when the centromere of chromosome 17 is also co-amplifed. Compared to FISH, in this study cohort D-ISH had a significant false negative rate for the detection of HER2 amplification. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD02-05.

Abstract Background: Cognitive changes for older women who receive chemotherapy are poorly understood. Methods: Cancer and Leukemia Group B (CALGB) 49907 enrolled 633 women ≥65 years with early stage breast cancer and randomized them to standard adjuvant chemotherapy (AC or CMF) or capecitabine (N Eng J Med 360:2055, 2009). Patients enrolled on the Quality of Life companion study (N = 350) included women who had cognitive and psychological functioning sufficient for providing informed consent and participation in the trial (J Clin Oncol 29:1022, 2011). Participants completed an 18 item questionnaire focusing on their subjective report of cognitive function (attention, problem-solving, speed, new learning, and remote memory) at 6 time points (baseline, mid-treatment, within 1 month post treatment, and at 12, 18, and 24 months post treatment). Possible scores for each item ranged from 1–7 (‘above average’ - ‘severe problem’). Cognitive function score (CFS) was defined as the mean score of items 1–18. Cognitive impairment was defined as CFS 1.5 standard deviations above the overall average baseline. Univariate associations were tested between baseline CFS and patient characteristics (treatment, race, education, number of positive nodes, hormone receptor status, HER2 status, performance status, number of comorbidities, fatigue and depression) using Kruskal-Wallis testing. Frequency distributions were used to describe cognitive impairment. Multivariate analyses were not completed because few women reported subjective cognitive impairment during the study period. Results: 297 assessments were received at baseline, 280 at both mid-treatment and within 1 month post-treatment, 259 at 12 months, 245 at 18 months and 240 at 24 months post-treatment. The median age was 72 (65–85); 32% received AC, 21% CMF, and 47% capecitabine. Most women were white (87%) and had a performance status of 0 (73%). Approximately half of women had a high school degree or less and the majority had stage I-II (78%), hormone-receptor positive (68%) cancers and most did not experience depression or fatigue at baseline. At baseline, the overall mean CFS was 2.1 (‘normal ability’) and 19 women (6%) had mild to severe impairment. Baseline scores did not differ by treatment (p = 0.35). Worse cognitive function at baseline was associated with less education (p < 0.01), increased number of positive nodes (p = 0.02), 4+ comorbid conditions (p < 0.01) and fatigue (p = 0.02), although differences for these groups were small. During the study period, overall mean cognitive function scores remained at ‘normal ability’. At mid-treatment, within 1 month post treatment, 12, 18 and 24 months, cognitive impairment was present in 19 (6%), 19 (6%), 29 (10%), 31 (12%), 18 (7%), and 22 (9%), respectively. Conclusions: Our data suggest that in a healthy group of women without baseline cognitive impairments on objective screening, chemotherapy does not seem to be associated with changes in self-reported cognitive function over time. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-08-05.