William Grogan

Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.

BackgroundThe Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies.MethodsBaseline tumour biopsies were available from 74 patients with HER2-positive breast cancer who were enrolled in the phase II TCHL neoadjuvant study (ICORG 10-05) assessing TCH (docetaxel, carboplatin, trastuzumab) (n = 38) versus TCL (docetaxel, carboplatin, lapatinib) (n = 10) versus TCHL (docetaxel, carboplatin, trastuzumab, lapatinib) (n = 40), each for six cycles. Activating mutations in PIK3CA and ERBB family genes were identified using mass spectrometry-based genotyping. Phosphatase and tensin homolog (PTEN) expression was assessed by immunohistochemistry.ResultsPIK3CA and/or ERBB family mutations were detected in 23 (31.1%) tumour samples tested, whereas PTEN expression was low in 31.1% of cases tested. Mutation frequency was similar in each treatment arm (31.3% in TCH arm, 30% in TCL arm and 31.3% in TCHL arm) and was not influenced by oestrogen receptor (ER) status (27.6% in ER-negative patients, 33.3% in ER-positive patients) or progesterone receptor (PR) status (32.6% in PR-negative patients, 29% in PR-positive patients). There was no significant difference in pathological complete response (pCR) rates between 47 patients with wild-type (WT) tumours and 22 patients whose tumours carried mutations (in either PIK3CA or ERBB family genes) (42.5% vs. 54.5%; p = 0.439). Similarly, there was no significant difference in pCR rates between patients with PIK3CA/ERBB family mutated/PTEN-low (i.e., PI3K-activated) tumours and patients without PI3K activation (50% vs. 44%; p = 0.769). However, in the TCHL (but not the TCH) group, the pCR rate was higher for 9 patients with PIK3CA/ERBB family mutated tumours than for 20 patients with PIK3CA/ERBB family WT tumours (77.8% vs. 35%; p = 0.05).ConclusionsOur results indicate that patients who receive neoadjuvant TCHL and have PIK3CA/ERBB family mutated tumours may be more likely to have a pCR than patients with WT tumours.Trial registrationClinicalTrials.gov, NCT01485926. Registered on 2 December 2011.

Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer: Folfiri ± Regorafenib as Second-Line Therapy

Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double‐blind, placebo‐controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second‐line treatment for metastatic colorectal cancer.

Mutational analysis of clinically relevant cancer related genes in colorectal cancer.

615 Background: Whole genome sequencing of colorectal cancer (CRC) has identified common mutations that have been implicated in tumorigenesis. We investigated the association between genetic mutations in known cancer related signaling pathways, and clinicopathological variables in patients with CRC. Methods: DNA samples of patients with CRC were genotyped for Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations using the Sequenom platform. Results: Tissue from 68 patients was genotyped. 163 mutations were identified in 21 cancer related genes. 45% of patients had stage III CRC & 10% had stage IV CRC at diagnosis. 17 patients developed metastatic CRC. 59 patients had at least 1 mutation. Mutations occurring in at least 5% of patients included KRAS(35%), PIK3R1(34%), TP53(32%), PHLPP2(32%), BRAF(16%), PIK3CA(13%), APC(13%), IDH1(12%), FBXW(7%) & MET(6%). Less frequent mutations (<5%) included GNAS, PTPN, NRAS, STK11, TBX3, and EGFR. KRAS mutations were associated with m...

1546PASSESSMENT OF OLDER PATIENTS WITH CANCER: EDMONTON FRAIL SCALE (EFS) AS A PREDICTOR OF ADVERSE OUTCOMES IN A COHORT OF OLDER PATIENTS UNDERGOING SYSTEMIC THERAPY

ABSTRACT Aim: Older cancer patients (pts) are at risk of toxicity from systemic therapy (ST). The EFS is a geriatric tool assessing frailty covering: Cognition, Health, Independence, Performance, Social, Medications, Nutrition, Mood, and Continence. It is unknown if the EFS can predict toxicity in pts who have already been selected for ST. Prospectively we examined the EFS as a predictor of adverse outcomes in older pts undergoing ST. Methods: Candidates seen by a Medical Oncologist and deemed appropriate for ST ≥65years, starting new ST were included. EFS, demographics, diagnosis, ECOG performance status (PS) and adverse events using the NCI CTCAE v4.03 were assessed. The association between EFS and toxicity was examined during one treatment cycle using Pearsons correlation coefficient (r). Results: From Feb-April 2014, 24 pts were included (table), median age 72 years (65–92). EFS results were; No frailty 10 (42%), Apparently vulnerable 8 (33%), Mild frailty 4 (17%), Moderate frailty 1 (4%) and Severe frailty 1 (4%). Many were of good PS (54% had ECOG 1). All toxicities were recorded with most common non-lab toxicities being fatigue 12 (50%) and pain 8 (33%), all ≤grade III. The most common lab toxicities were Hb and Alk Phos. During ST there were 3 (13%) admissions, 6 (25%) had treatments held or dose adjustments and 1 death occurred. Age and ECOG were significantly correlated (r=0.43, p = Patient Characteristics N % Sex Male 10 42 Female 14 58 Marital Status Married 10 42 Widowed 8 33 Single 4 17 Divorced / separated 2 8 Work Status Retired 22 92 Part-time employed 1 4 Other 1 4 Cancer Diagnosis Colorectal 6 25 Breast 6 25 Other GI 3 13 Lung 3 13 Genitourinary 2 8 Others 4 17 Stage I-III 12 50 IV 11 46 N/A (Brain) 1 4 Conclusions: Preliminary results suggest elevated EFS score is associated with toxicities during the first cycle of ST. Quantifying frailty could aid formation of a predictive model for adverse events in the geriatric population. Disclosure: P. Morris: Dr Patrick Morris; Honouraria GSK and Nordic. All other authors have declared no conflicts of interest.

1377PPATTERNS OF TREATMENT AND RATES OF ADMISSION IN A SPECIALIST ONCOLOGY CLINIC

ABSTRACT Aim: Medical Oncology practices face greater demand on services, with increased focus on Day Care Treatments and oral therapies. To address this, we recently developed specialist oral chemotherapy clinics (SOCC) and instigated an Electronic Patient Record (EPR) system. We examined treatment patterns, admission rates and impact of SOCC in a tertiary referral centre with a Neuro-Oncology interest. Summary results of data CNS Breast Lung Colorectal Upper GI N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Encounters 199 626 257 413 235 Chemotherapy 188 (95) 549 (88) 207 (80) 361 (87) 185 (79) Intravenous 70 (37) 528 (96) 193 (93) 352 (97) 181 (98) Oral 118 (73) 21 (4) 14 (7) 9 (3) 4 (2) Procedures 0 8 (1) 2 (1) 7 (2) 1 (0.5) 0 Urgent Care 11 (5) 69 (11) 48 (19) 45 (11) 49 (21) Admitted 5 (45) 10 (15) 9 (19) 6 (13) 10 (20) Discharged 6 (55) 59 (85) 39 (81) 39 (87) 39 (80) Methods: Using the EPR, we developed a questionnaire and prospectively examined each patient encounter. This form was used to collect information on disease type and reason for encounter: 1) IV therapy, 2) oral therapy, 3) urgent care (admit/discharge), 4) procedure. Patterns of attendance were examined for common malignancies; Central Nervous System (CNS), Breast, Lung, Colorectal, Gastrointestinal (GI) cancers. Data were compared using Fischers Exact Test. Results: Between August and December 2013, 1,730 encounters were recorded. The breakdown by disease subtype was: Breast 626 (35%), Colorectal 413 (24%), Lung 257 (15%), Upper GI 235 (14%), CNS 199 (12%). Across all disease types, most encounters were for chemotherapy (table 1). Oral chemotherapy encounters were more frequent in CNS patients than other diseases (73% vs 4%, p Conclusions: The use of the Oncology Day Ward as an urgent care centre facilitates patient discharge. This study highlights the high rate of oral chemotherapy usage in patients with CNS malignancies. SOCC may be of benefit in these patients, providing regular specialist care, as evidenced by the low urgent care rate. Patients with lung or upper GI cancers were more likely to present for urgent care, highlighting the need for a supportive care structure in this population. Disclosure: All authors have declared no conflicts of interest.

Influence of ABO blood group on the natural history of advanced pancreatic adenocarcinoma (PC).

307 Background: An association between blood group (ABO) and PC has been demonstrated at epidemiologic and genomic levels. Variations in ABO type may lead to higher pro-inflammatory cytokines levels with modifications in cellular adhesionand signalling promoting carcinogenesis. This study investigated the influence of ABO on the clinical behaviour of advanced PC in patients (pts) , treated with chemotherapy (ctx). Methods: Pts with confirmed PC were identified from 4 institutional databases. Inclusion criteria were unresectable (UPC) or metastatic disease (MPC), receipt of ctx and availability of ABO data. Clinicopathologic details were collected. 200 random anonymied non-cancer ABO samples were collected as control. Descriptive statistics and survival analyses were performed. Results: Between 2001 and 2012, 222 pts met inclusion criteria. Median age was 63 years (range: 33 – 83) 56% were males. 60% of pts had MPC and 27% received doublet ctx. ABO distribution was: A (40%), AB (5%), B (11%) and O (44%). T...