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Purpose:RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer.Patients and Methods:Patients with advanced ER+/HER2− breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion.Results:Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0–11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%–42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%–68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%–40.7%), median DoR 6.9 months (IQR 5.9–13.1), and CBR 52.0% (95% CI, 31.3%–72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index.Conclusions:Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.

Supplementary Table from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer

Supplementary Data from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer

Supplementary Figure from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer

Background The optimal treatment and molecular landscape of recurrent clear cell carcinoma of the vulva (VCCC) are unknown. No reported data exist regarding the efficacy of anti-programmed death 1 (PD-1) immune checkpoint inhibition in VCCC. We report on a patient with chemotherapy-refractory recurrent VCCC, who was found to have high tumor programmed death-ligand 1 (PD-L1) combined positive score (CPS), and subsequently experienced a durable partial response (PR), after treatment with off-label fifth-line pembrolizumab. Case presentation A forty-year-old Filipino woman presented to our center with recurrent VCCC that had progressed on multiple prior lines of cytotoxic chemotherapy. She had a large 25 cm fungating left groin tumor causing marked lower limb lymphedema, pain and limited mobility. PD-L1 CPS by immunohistochemistry was 45. She was treated with off-label pembrolizumab monotherapy and had a dramatic clinical, biochemical and radiological partial response. The progression-free survival of this patient's VCCC after treatment with pembrolizumab, defined as the time from initiation of pembrolizumab until disease progression (by Response Evaluation Criteria in Solid Tumors (version 1.1)), was 8 months. While receiving pembrolizumab, she was diagnosed with concurrent secondary myelodysplastic syndrome with excess blasts (MDS-EB), thought to be related to her prior exposure to multiple lines of cytotoxic chemotherapy. This eventually progressed to acute myeloid leukemia (AML), leading to her demise. Overall survival from time of initiation of pembrolizumab till death was 16 months. Conclusion Pembrolizumab was active in this patient with chemotherapy-refractory VCCC which harbored high PD-L1 CPS. Further studies to determine the role of immune check-point blockade in the treatment of VCCC are warranted.

Purpose: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer. Patients and Methods: Patients with advanced ER+/HER2− breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion. Results: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0–11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%–42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%–68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%–40.7%), median DoR 6.9 months (IQR 5.9–13.1), and CBR 52.0% (95% CI, 31.3%–72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index. Conclusions: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.

Purpose Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). Methods and Materials Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. Results A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. Conclusions The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.

6086 Background: Precision oncology approaches in EC patients (pts) are evolving with emerging targeted therapy. We reviewed the effect of genomic findings on treatment choice and outcome in an Asian EC cohort. Methods: Recurrent or metastatic ECs were prospectively profiled with next-generation sequencing (NGS) and relevant immunohistochemistry. Clinical data were collected to assess outcomes. Results: Between 12/2014 to 12/2019, 51 Asian EC pts of endometrioid (26/51), serous (7/51), carcinosarcoma (4/51), clear cell (4/51) and mixed (10/51) histology were enrolled. 35/51(69%) of tumors were high grade. The median age at diagnosis was 56 (range 37-77), and the median lines of treatment received was 3 (range 1-8). 45/51(88%) of pts had successful NGS profiling, 31/45(69%) using FoundationOne CDx, and 14/45 (31%) on an in-house platform. Frequent mutations (>20%) occurred in PTEN (60%), PIK3CA (49%), TP53 (46%), ARID1A (27%), CTNNB1 (24%) and KRAS (22%). There were 12/51(24%) MSI-H, 25/51(49%) MSS, and 14/51(27%) MSI-unknown tumors. The 6 mth progression free survival (PFS) rate for MSS versus MSI-H pts treated with front-line carboplatin+paclitaxel (CP) was 83% versus 50% (RR 1.67, fisher’s exact 2-sided p=0.09), with a shorter median PFS after 1st line CP for MSI-H versus MSS pts (median 5.2 mth vs. 8.3 mth, not sig). Upon progression, 29/51(57%) of pts were matched to therapy based on tumor profiles. Of these, 7/29(24%), 13/29(45%) and 9/29(31%) matched to anti-PD1/PD-L1, endocrine therapy and other targeted therapy, respectively. Among 7 MSI-H pts matched to anti-PD1/PD-L1 therapy, median PFS was 14.6 mth (95% CI 0.4-29), and objective response rate was 57%(4/7). In subsequent-line, matching to endocrine therapy (HR 4.3 95% CI 0.95-19.0, p=0.06) or other targeted therapy (HR 5.1, 95% CI 1.1-24.5, p=0.04) was associated with worse PFS compared to anti-PD1/PD-L1 therapy. Despite a short median PFS after front-line CP, median overall survival (OS) was not reached for MSI-H pts, compared to 38 mth (95% CI 30.7-46.0) for MSS and MSI-unknown pts. Conclusions: MSI-H EC pts appear to have shorter PFS to front-line CP chemotherapy compared with MSS pts, but may derive durable responses from immunotherapy in subsequent-line therapy. Early use of immunotherapy in advanced MSI-H EC pts should be considered. Further optimisation of therapy is urgently needed in advanced MSS EC.

3561 Background: Somatic profiling of MBC has highlighted actionable mutations and driven trials of matched targeted therapy (tx). Previous phase I studies have reported improved outcomes following matched therapies with tumour molecular profiles. Here, we review next generation sequencing (NGS) and treatment outcomes of Asian MBC patients (pts) in the phase I unit of a tertiary centre. Methods: Pts with MBC referred to a phase I unit underwent NGS (n = 152). Tumour tissue was sequenced via the amplicon based Ion Ampliseq Cancer (IAC) v2 (50 genes) platform from 2014-2017 prior to institutional change to Foundation Medicine 1 (FM1) (324 genes) 2017-2019. Patients were counselled on findings and enrolled onto matched therapeutic trials where available. Results: NGS was successfully performed in 107 pts (IAC 46%, FM1 54%) of which tumour subtypes include hormone receptor positive 63%, triple negative breast cancer (TNBC) 28% and Her2 positive 19%. Median lines of prior tx for MBC was 4 (range 0-12). 89% had prior chemotherapy (CT), 57% prior endocrine therapy (ET). 72/107 (67%) sequenced patients had further treatment and 18 (25%) were matched to tx based on NGS findings (15 clinical trial, 3 off trial). Matching rates on both NGS platforms were similar (IAC 22% vs FM1 28%). Mutated pathways with potential matched tx included PIK3CA/AKT/PTEN (52%), DNA damage response (DRR) (15%), and FGFR (11%) pathways. PIK3 mutations were seen in 43% and associated with higher number of metastatic sites (p = 0.03); most prevalent aberrations were PIK3CA H1047R (41%) and PIK3CA E542K (13%). Matched cases were more heavily pretreated (mean lines of prior tx 5.3 matched vs 3.7, unmatched p = 0.05), and showed a median progression free survival (mPFS) of 24 weeks [w] and clinical benefit rate (complete/partial response or stable disease ≥ 12 weeks) of 53% on matched tx. Comparison by NGS platform showed improved mPFS for matched vs unmatched pts sequenced on FM1 vs IAC (FM1: 26 vs 19w, HR = 0.76 [95% CI: 0.3-1.9]; IAC: 8 vs 12w; HR = 1.21 [95% CI: 0.5-2.8]). Interestingly, 1 pt with SMARCB mutation, reportedly associated with the FGFR pathway, had a PFS of 70w on tx with a pan-FGFR inhibitor after progressing on 3 prior lines of tx (ET and CT). Conclusions: Molecular profiling of MBC in a phase I unit led to matched tx in 25% of cases. Matched pts showed encouraging mPFS with a suggestion of benefit in those matched after sequencing on a broader gene panel (FM1).

// Gloria H.J. Chan 1, * , Pei Yi Ong 1, * , Jeffrey J.H. Low 2 , Hwai Loong Kong 1 , Samuel G.W. Ow 1 , David S.P. Tan 1, 3 , Yi Wan Lim 1 , Siew Eng Lim 1 and Soo-Chin Lee 1, 3 1 Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore 2 Department of Obstetrics and Gynaecology, National University Hospital, Singapore 3 Cancer Science Institute, Singapore * These authors have contributed equally to this work Correspondence to: Soo-Chin Lee, email: csilsc@nus.edu.sg Keywords: genetic testing; germ-line mutation; neoplasms; multiple primary/diagnosis Received: May 22, 2018 Accepted: June 23, 2018 Published: July 17, 2018 ABSTRACT Background: Developing multiple cancers is an indicator of underlying hereditary cancer predisposition, but there is a paucity of data regarding the clinical genetic testing outcomes of these patients. Methods: We compared cancer index patients with ≥2 primary malignancies versus 1 primary cancer who underwent clinical evaluation and testing with multi-gene panels comprising up to 49 genes from 1998-2016. Results: Among 1191 cancer index patients, 80.6%, 17.2%, and 2.2% respectively had 1, 2, and ≥3 primary malignancies. For patients with 2 primary cancers (n=205), the most common cancer pairs were bilateral breast (37.5%), breast-ovary (11.7%), endometrium-ovary (9.2%), colon-endometrium (3.9%) and colon-colon (3.4%). 42.3% patients underwent gene testing including 110/231 (47.6%) with multiple malignancies. Pathogenic variants were found more frequently in younger patients, in those with a family history of cancer related to the suspected syndrome, and a trend towards significance in those with multiple primary cancers (35.5% vs. 25.6%, p = 0.09). In patients with multiple cancers, pathogenic variants were most commonly identified in BRCA1 (38.5%), BRCA2 (17.9%), and the mismatch repair genes (20.5%), while 23.1% of pathogenic mutations were in other moderate- to high-penetrance cancer predisposition genes including APC, ATM, MUTYH, PALB2, RAD50 and TP53. Conclusion: Patients with multiple cancers were more likely to carry pathogenic mutations than those with single cancer. About three-quarters of deleterious mutations in patients with multiple primary cancers were in BRCA1/2 and the mismatch repair genes, but multi-gene panel testing facilitated the detection of mutations in another 6 genes and is warranted in this high-risk population.

Objectives Vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer. Methods Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes. Results Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele. Conclusion UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat, and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen.

Studying chemotherapy-induced gene expression changes in vivo, which could provide insights into mechanisms of chemotherapy resistance.We analyzed and compared tumor gene expression changes of about 38 500 genes before and 3 weeks after doxorubicin or docetaxel treatment in 47 breast cancer patients.By using the median expression level of each probe set as the parameter, less than 5% of genes were upregulated or downregulated by more than 50% after treatment with either drug. Doxorubicin and docetaxel concordantly induced 251 genes predominantly involved in protein and macromolecule metabolism (upregulated), and cell cycle and DNA/RNA metabolism (downregulated). Doxorubicin treatment resulted in coregulation of a cluster of 345 probe sets involved in focal adhesion, Jak-Stat signaling pathway, cell adhesion molecules, and natural killer cell mediated cytotoxicity, whereas docetaxel treatment resulted in coregulation of a cluster of 448 probe sets involved in focal adhesion, neurodegenerative disorders, sphingolipid metabolism, and cell cycle. Tumors that were intrinsically sensitive or resistant to doxorubicin or docetaxel evoked distinct gene expression changes in response to the drug; doxorubicin-resistant tumors upregulated genes that were enriched for ErbB signaling, ubiquitin-mediated proteolysis, TGF-beta signaling, and MAP-kinase signaling pathways, whereas docetaxel-resistant tumors upregulated genes that were enriched for focal adhesion and regulation of actin cytoskeleton. The drug-specific tumor gene expression changes were validated in independent in-vitro and in-vivo datasets.Gene expression alterations of breast cancer were specific to doxorubicin and docetaxel treatment, and yielded mechanistic insights into resistance to either drug. Gene expression analysis provides more global perspectives on resistance pathways that could be exploited for therapeutic selection.

1512 Background: Developing multiple primary cancers is an indicator of underlying hereditary cancer predisposition, but there is a paucity of data regarding the characteristics and clinical genetic testing outcome of these patients. Methods: We compared cancer index patients with 1 vs > 1 primary malignancy who underwent evaluation and clinical testing with multi-gene panels comprising up to 49 genes in a cancer genetics clinic in a tertiary cancer centre in Asia from 1998-2016. Results: Among 1191 cancer index patients, 960 (80.6%), 205 (17.2%), and 26 (2.2%) respectively had 1, 2, and ≥3 primary malignancies. Among patients with > 1 primary cancers (n = 231), the most common cancer pairs were breast-breast (35.4%), breast-ovary (12.1%), endometrium-ovary (8.2%), colon-colon (2.4%) and, colon-endometrium (2.4%). The mean age at diagnosis of the first, second and third cancers were 46.0 (21 to 87), 52.1 (21 to 89) and 57.7 (41 to 83) respectively. The mean duration between first and second cancers is 6.0 years (0 to 32). The most commonly suspected syndromes in patients with 1 vs > 1 primary cancer were hereditary breast and ovarian cancer 63.8% vs 53.6%, Lynch 24.8% vs 31.1%, Li-Fraumeni syndromes 1.8% vs 1.7%, and others 9.3% vs 13.4% (p = 0.03). Patients with > 1 primary cancer were more likely to have > 20% a priori risk of suspected hereditary cancer syndrome (42.8% vs. 26.5%; p < 0.001). 504/1191 (42.3%) patients underwent gene testing, including 394/960 (41.0%) and 110/231 (47.6%) patients with 1 vs > 1 cancer. Deleterious mutations were more likely to be identified in patients with > 1 vs 1 cancer (34.5% vs. 25.8%; p = 0.073), with causative genes being BRCA1 38.5%, BRCA2 17.9%, MLH1/MSH2/MSH6 20.5%, TP53 7.7%, and others (ATM [n = 2], MUTYH, APC, PALB2, RAD51 [n = 1 each]) for patients with > 1 cancer. VUS rates were 31.7% vs.31.8% in patients with 1 vs > 1 cancer, and were identified in genes including BRIP1, CHEK2, PALLD, POLE, PTEN, STK11, SMARCA4, and VHL. Conclusions: Patients with > 1 primary cancer comprised one-fifth of cancer index patients evaluated at a cancer genetics clinic, and were more likely to be found with deleterious mutations than patients with only 1 cancer on multi-gene panel testing.

1056 Background: The active metabolite of Exe, 17-dihydroexemestane (17DhExe), is glucuronidated by UGT2B17 to inactive exemestane-17-O-glucuronide (Exe17- O-glu). UGT2B17*2/*2null genotype is 7 times more common in Asians than Caucasians and leads to reduced Exe glucuronidation in vitro. We studied Exe PK and PD in MBC patients genotyped for UGT2B17. Methods: Eligible patients (HR+ MBC; ≥1 line of endocrine therapy) received Exe 25mg OD till progression. UGBT2B17 genotype was correlated with day 29 (D29) steady-state PK (Exe and metabolites), change in PD biomarkers (estrone and androstenedione) at D29 vs baseline (BL), objective response rate (ORR) [sum of complete and partial responses], and clinical benefit rate (CBR) [response or stable disease ≥ 24 weeks]. Results: In 64 patients enrolled, CBR was 25%; ORR was 3%. Frequencies of UGT2B17*2/*2, UGT2B17*1/*2 and UGT2B17*1/*1 were 72%, 26% and 2%, respectively. PD and PK data were available for 54 and 53 patients respectively. Mean Exe17- O-glu AUC and Cmax were significantly lower, and mean 17DhExe Cmax numerically higher in patients with UGT2B17*2/*2 vs other genotypes (Table 1). 17DhExe Cmax was higher in patients with clinical benefit vs none (5.6 vs 3.8 ng/ml, p=0.02). Frequency of desired PD effect (rise in androstenedione and fall in estrone at D29 vs BL) was 22%. Exe plasma active index (PAI) [Table 1] was higher in patients with a fall in D29 estrone vs those without (14.7 vs 9.5, p=0.05). Conclusions: UGT2B17 genotype affects Exe PK and may have significant PD correlates. Larger studies to examine effects on clinical treatment efficacy are needed. Clinical trial information: NCT01655004. [Table: see text]

Objective Tumor gene expression signatures have been used to classify, prognosticate, and predict chemotherapy sensitivity in breast cancer, although almost all efforts have been focused on the unchallenged baseline tumor. Most cancer patients receive systemic therapy, and exposure to drug may modify the tumor's short-term and long-term outcomes. Drug-induced tumor gene signatures may thus be more predictive of treatment outcomes than the unperturbed tumor gene signatures. Methods Using a set of 47 breast cancer patients, we obtained paired prechemotherapy and postchemotherapy tumor biopsies and developed gene panels of baseline tumor (T1), postchemotherapy tumor (T2), and chemotherapy-induced relative change signatures (TDelta) to predict pathological response and progression-free survival (PFS). The signatures were validated in two independent test sets with paired prechemotherapy and postchemotherapy tumor samples, comprising of 18-20 patients each. Results T2 and TDelta were superior to T1 signatures in predicting for PFS (area under the curve of receiver operating characteristic 0.770 and 0.660 vs. 0.530) and pathological response (area under the curve of receiver operating characteristic 0.631 and 0.462 vs. 0.446) in the validation sets. In multivariate analysis for PFS with other clinical predictors, T2, but not T1, signatures remained as significant independent predictors. Conclusion Postchemotherapy tumor gene signatures outperformed baseline signatures and clinical predictors in predicting for pathological response and PFS, independent of clinical and pathological response to chemotherapy. Drug-induced tumor gene signatures may be more informative than unchallenged signatures in predicting treatment outcomes. These findings challenge the current practice of relying only on the baseline tumor to predict outcome, which overlooks the contributions of therapeutic interventions.

619^ Background: The optimal neoadjuvant regimen in HER2+ breast cancer is undefined. We evaluated the efficacy and tolerability of weekly paclitaxel/carboplatin with lapatinib. Methods: HER2+ stage I-III breast cancer patients received 4 cycles of 3 weekly PCL [IV paclitaxel (P) 80mg/m2 (days 1, 8, 15), carboplatin (C) AUC 2 (days 1, 8), oral lapatinib (L) (750mg daily)] followed by surgery. Lapatinib dose reductions were not allowed. Patients with pCR (ypT0N0) received 2 cycles of adjuvant PCL; those without received 4 cycles of doxorubicin/cyclophosphamide. All received 1 year of adjuvant trastuzumab and at investigators’ discretion, concurrent lapatinib 1000mg/day for 52 weeks (neoadjuvant + adjuvant). Primary endpoint was pCR; secondary endpoints were clinical CR/PR, toxicities and DFS. Results: 36 patients were recruited (Chinese/Malay/Others: 52.8/36.1/11.1%). Median age at diagnosis was 51 (29-78) years. 69.4%, 63.9%, 80.6% and 61.1% had cT3/4, cN+, grade 3 and hormone receptor positive tumors. 63...

2526 Background: Use of concomitant medications that inhibit drug metabolizing enzymes such as Cyp3A4 is common and may affect chemotherapy PK/PD. We studied the effects of Cyp3A4 inhibition with ketoconazole on docetaxel PK/PD in 3 Asian ethnic groups. Methods: Two cohorts of chemonaive breast cancer patients were compared. The first cohort comprised of 95 patients (62 Chinese, 26 Malay, 7 Indian) treated with 75mg/m2 docetaxel unmodulated by ketoconazole, while the second cohort comprised of 31 patients (14 Chinese, 14 Malay, 3 Indian) treated with docetaxel 70mg flat dose modulated by oral ketoconazole, a regimen we previously reported to result in comparable docetaxel AUC as 75mg/m2 docetaxel. Plasma docetaxel concentrations were obtained at 0, 0.5, 1, 2, 5, 7 and 24 hours, and blood counts monitored on days 8 and 15 of cycle 1. Results: No significant differences in docetaxel PK or neutropenia between the races were observed in response to 75mg/m2 docetaxel unmodulated by ketoconazole (docetaxel clearance 36.4±16.9, 34.3±12.5, 44.2±27.7L/h, p=0.702; docetaxel AUC 3.6±2.7, 3.5±1.2, 2.9±1.3mg/L h, p=0.418; day 8 neutrophil count 0.5±0.6, 0.8±0.8, 0.4±0.3x109/L, p=0.138; grade 4 neutropenia 66%, 50%, 86%, p=0.157). In contrast, when docetaxel was administered with ketoconazole to inhibit Cyp3A4, inter-ethnic differences in docetaxel PK/PD were observed, with Chinese having the lowest docetaxel clearance and highest docetaxel AUC, followed by Malays and Indians (docetaxel clearance 18.6±5.7, 23.7±9.3, 30.6±6.7L/h, p=0.048; p=0.017 trend test; docetaxel AUC 4.2±1.4, 4.1±3.9, 2.4±0.5 mg/L h, p=0.048, p=0.017 trend test), although there were no statistically significant differences in body weight or surface area between the races. In concordance, Chinese patients experienced greatest degree of myelosuppression, followed by Malays and Indians (day 8 neutrophil count 0.8±0.8, 1.5±1.1, 1.7±1.1x109/L, p=0.046, p=0.013 trend test), and were more likely to develop grade 4 neutropenia (57%, 14%, 0%, p=0.024) from docetaxel + ketoconazole. Conclusions: Inter-ethnic differences in CYP3A inhibition by ketoconazole exist, and are important when evaluating the impact of concomitant medications with chemotherapy that may inhibit Cyp3A4. No significant financial relationships to disclose.