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PURPOSE Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates ( P < .0001) and 3-year overall survival (OS) rates ( P < .0001). TNBC was associated with increased risk for visceral metastases ( P = .0005), lower risk for bone recurrence ( P = .027), and shorter postrecurrence survival ( P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival ( P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC ( P < .0001). CONCLUSION Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

TPS819 Background: The gut microbiome (GM) is thought to influence host immunity by modulating multiple immunologic pathways. Studies have suggested that dysbiosis of the GM confers a predisposition to certain malignancies and influences response to immune checkpoint inhibitors. However, little is known about how the GM diversity influences complete pathological response to neoadjuvant therapy in gastrointestinal (GI) tumours. We hypothesize that a more diverse GM constitution at baseline will lead to improved pathological response at the time of definitive surgery. Methods: We designed a cross-institutional multi-center translational study investigating the impact of the GM diversity on the efficacy of neoadjuvant therapy in GI cancers by assessing its association with pathological response. The study population will consist of patients with an early-stage rectal or esophageal cancer due to commence neoadjuvant therapy (including chemotherapy and chemoradiation) and planned for definitive surgery. Patients who received prior chemotherapy/monoclonal antibodies/immune checkpoint inhibitors or radiation will be excluded. The study assessments will include fecal sampling of the GM prior to neoadjuvant therapy, upon completion and again six months post completion of therapy. Fecal samples will be analysed by 16S RNA sequencing. Pathological response will be examined at time of surgery and patients will be classified as responders (complete pathological response) or non-responders. The primary endpoint of the study is to examine the association between the GM diversity and pathological response. 120 patients will be recruited over 18 months. Results: Species richness (Alpha Diversity) will be analysed using the Shannon diversity index and Jaccard similarity index to calculate beta diversity. Classification and clustering analysis will be performed with Principal Component Analysis (PCA) and Random Forest analysis. Comparison of taxa or functions between clinical cohorts will be performed using the two tailed Z test and corrected using the false discovery rate to determine Q-values. The association between GM and complete pathological response will be examined using logistic regression analysis adjusting for potential confounding factors. Adjusted odds ratios (OR) and 95% confidence intervals will be presented. Conclusions: This study will show preliminary insights into the role of GM as a potential biomarker for neoadjuvant therapy efficacy in patients with GI cancers. Recruitment is on-going.

335 Background: In locally advanced esophageal cancer, neoadjuvant chemo-radiotherapy improves survival compared with surgery alone. In the Chemo-Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS), the median age was 60. However, 1/3 of patients diagnosed with esophageal cancer are over 70 years. The CROSS outcomes are therefore limited in its application to older patients. The objective of this study is to report and compare the outcomes and tolerability in elderly patients (≥70 years), who underwent neoadjuvant chemo-radiation for esophageal cancer with younger patients < 70 years. Methods: A retrospective analysis of patients treated with neoadjuvant chemo-radiation for esophageal cancer between 1st January 2015 and 1st January 2021 was completed. Baseline characteristics and haematological toxicities were reported. Pathological response was reported. Survival was estimated using the Kaplan-Meier method. Results: In total 105 patients were included; 35 (33%) were ≥ 70 years and 70 (67%) patients were < 70 years. In the elderly cohort, the median age was 75 (70-86) and the younger cohort median age was 60 (29-69). 73% of patients in each cohort were male. 31 (89%) of older adults experienced any grade of anaemia compared with 45 (64%) of the younger cohort. Only one patient experienced ≥ grade 3 anaemia in each cohort. 18(51%) and 33(47%) of older and younger patients respectively experienced any grade of neutropenia. 5(14%) older and 7(10%) younger patients experienced ≥ grade 3 neutropenia. 15(43%) and 43(61%) of older and younger patients experienced any grade of thrombocytopenia. No patients experienced ≥ grade 3 thrombocytopenia. 80% of the older and 86% of the younger cohort proceeded to surgery. 3(11%) and 17(29%) of the older and younger cohorts respectively who underwent surgery achieved a complete pathological response. There was no difference in overall survival (OS) between the cohorts (p=0.48). There was also no difference in progression free survival (PFS) between the cohorts. Conclusions: In conclusion, we confirm that neoadjuvant chemo-radiation is tolerable in patients ≥ 70 when compared with patients < 70 years. Both OS and PFS is similar in both cohorts. We recommend the use of neoadjuvant therapy in appropriately selected patients ≥ 70 years.

167 Background: Multiple activating genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways have been implicated in the development of resistance to anti-cancer therapies. Ribociclib has limited activity as a single agent in CRC. However, combining Ribociclib with targeted therapies of the MAPK and PI3K pathways may be a promising treatment strategy for CRC. Methods: We explored the in vitro efficacy of drug combinations Ribociclib (R) and Alpelisib (A) in four CRC cell lines with different mutational status; CACO2 ( PIK3CA/KRAS wild-type), LS1034 ( KRAS mutated), SNUC4 ( PIK3CA mutated) and DLD1 ( PIK3CA/KRAS mutated). Drug combination index (CI) was calculated using Calcusyn Biosoft software. We used a western immunoblotting method for protein analysis. The Chick Chorio-Allantoic Membrane (CAM) assay was used for in-vivo analysis of the effect of the drug combination. Results: IC50s for R and A were calculated for all four cell lines. CACO2 and DLD1 cells were resistant to Ribociclib (IC50 > 15µM). The cell lines had varying sensitivity to both drugs. Drug combination analysis showed that the combination of R and A has a synergistic anti-proliferative effect in all CRC cell lines tested. The combination of R and A is highly synergistic in LS1034 cells which harbour a KRAS mutation (CI = 0.16). Relative expression of the proteins Cyclin D1, E2F-1, p-BCL-2, p-AKT, p-Rb and p-S6 was determined by measuring the density of each band from the western blot experiments and normalizing to β-actin. Combined inhibition of CDK4/6 and PI3Kα caused a simultaneous reduction of p-RB, p-AKT and p-S6 and a more complete inhibition of the PI3K/AKT/mTOR pathway in all four cell lines tested. There was also an increase in the expression of the apoptotic marker pBCL2 in cells treated with the combination of R and A compared to vehicle control(VC). We observed a macroscopic reduction of visible tumour in all cell lines treated with the R and A combination in vivo as compared to VC. Microscopic examination also showed less Ki67 staining and negative cytokeratin staining in combination treated groups. Conclusions: We see a synergistic response to treatment with the combination of R and A in all cell lines and this combination may be a rational treatment strategy in colorectal cancer.

e14037 Background: (MGMT) promotor is prognostic and predictive of temozolomide (TMZ) benefit in newly diagnosed GBM. It has been suggested that MGMT methylation is associated with TMZ toxicity in some cancers such as melanoma but is not clearly defined in GBM. Methods: To investigate this, a retrospective electronic chart review of patients (pts) with resected GBM in a tertiary neurosurgical referral center from 1 July 2017 – 31 Dec 2020 was conducted. Hematological toxicities during TMZ with RT (concurrent) and subsequent TMZ (adjuvant) were assessed and graded by CTCAE V5.0. Toxicity was compared by MGMT methylation status. Results: In a 3.5 year period, 417 GBM resections were performed. Of these, 186 (45%) patients received at least 1 dose of TMZ in our institution: 180 pts received concurrent TMZ, 6 pts received adjuvant only. MGMT was methylated, unmethylated and unknown in 72, 97 and 17 pts respectively. In the concurrent and adjuvant phases respectively, thrombocytopenia incidence was 20%(N=14) and 52%(N=25) in the methylated group and 15%(N=15) and 51%(N=37) in the unmethylated group. In the adjuvant phase, incidence of ≥ grade 3 thrombocytopenia was 8%(N=4), in the methylated patients and 9%(N=7) for those unmethylated. Neutropenia incidence was low in the concurrent phase, however in the adjuvant phase was 29%(N=14) in the methylated group and 23%(N=17) in the unmethylated group. ≥G3 incidence was 10%(N=5) and 3%(N=2) respectively. Conclusions: In this retrospective study, a higher incidence of hematological toxicity was not seen in pts with MGMT methylated tumors. Methylation of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase.[Table: see text]

e15041 Background: The treatment of HER2+ breast cancer (BC) has improved substantially with the use of targeted therapies, and patients achieving pathological complete response (pCR) following neoadjuvant therapy have significantly improved disease free survival. However, there is currently no way to determine which patients are most likely to respond to neoadjuvant HER2-targeting treatment. Growing evidence indicates tumour infiltrating lymphocytes influence HER2+ BC outcome. We hypothesize that a deeper investigation of the immune landscape of HER2+ patient tumours may improve patient stratification and identify an immune profile associated with pCR. Methods: 3plex immunohistochemistry panels identifying immune cell subpopulations and tertiary lymphoid structures were applied to HER2+ BC tumors (pre-treatment N=19, post-treatment N=9) of patients of the neoadjuvant TCHL clinical trial (NCT01485926), who received HER2-targeting therapy. Quantitative analysis of CD3+, CD20+, DC-Lamp+, CD4+, and CD8+ immune cells on multi-labelled whole-slide images of TCHL tumor sections was performed using artificial intelligence image analysis models. Patient-specific densities of each cell type in tumor regions were determined to facilitate assessment of pre-treatment differences in target immune subpopulations in complete, partial, and non-responders. Results: Statistical analysis demonstrated a trend for higher densities of each immune subpopulation in pre-treatment biopsies of pCR vs. non-pCR patients. Patient categorisation based on median threshold demonstrated patients achieving pCR are more frequently high for each immune cell type assessed, while non-pCR patients are more frequently in the low category. Investigation of association of pre-treatment immune infiltrate with clinicopathological features demonstrated trends for higher levels of T-cell infiltration in later stage and hormone receptor negative patients. Conclusions: Multiplex IHC is an optimal technique for the concurrent assessment of multiple target markers in patient tissue, which can be quantitatively analyzed in a high throughput manner using AI models. The findings of this preliminary study support recent evidence regarding the role of tumor infiltrating immune cells in HER2+ BC outcome and warrant further investigation in a larger cohort.

e24178 Background: Medicinal cannabis is currently approved for symptom control in cancer patients. There is limited evidence to suggest cannabis is efficacious in the treatment of cancer. In this study we aim to characterise the extent of cannabis use in patients receiving anti-cancer therapies and what impact they think cannabis use has on their cancer. Methods: An anonymous survey was distributed to patients with cancer attending the Beaumont Hospital Oncology Day Unit for anti-cancer therapy over a period of 4 weeks. Results: 175 patients completed the survey. 166 (95%) of patients said they would be comfortable talking to their oncologist about cannabis use. 161 (92%) felt their oncologist should prescribe cannabis as part of their cancer treatment. 17% thought cannabis would cure their cancer. 38% thought cannabis would slow the growth of their cancer and 33% thought cannabis would treat cancer related symptoms. 42 (24%) of all patients had tried some form of cannabis at least once in their life. 26 (15%) were actively taking CBD (Cannabidiol) oil as part of their treatment independently of any healthcare professional guidance. More females (15) were taking CBD compared to males (11). A higher proportion of patients < 50 years (14) were taking CBD during their treatment. 30% of patients using CBD had breast cancer and 23% had a primary CNS malignancy. Of the patients taking CBD, 20 (77%) patients felt it would cure or slow cancer growth and 10 (38%) patients believed it would help with cancer related symptoms. Conclusions: Patients with cancer appear to have a positive attitude towards cannabis as part of their treatment despite limited evidence to support this. With the increasing availability of cannabis-based products globally, medical oncologists must now take into consideration patient’s attitude towards cannabis while treating their cancer. [Table: see text]

e24187 Background: Systemic treatments can improve symptom burden and prolong life in patients with advanced cancer. However, these therapies come with associated toxicities and in some cases can result in reduced quality of life for patients with no possibility of cure. International data has suggested that this cohort of patients have a poor understanding surrounding the goals of treatment in the advanced disease setting. We aimed to evaluate the expectations for cure and palliation from systemic therapies among patients with advanced, incurable cancer in our institution. Methods: Patients on active treatment attending the Oncology Day Ward completed anonymous questionnaires over a four week period. Personal demographics, decision making for treatment and expectation of benefit and toxicity was assessed. Analysis was carried out on patients assessed to have advanced metastatic disease. Results: 254 patients completed the questionnaire. 217 patients were assessed to have metastatic/incurable disease based on responses. 57% were male, 56% were age 30-64 and 35% had completed university level education. 42% of patients stated that treatment was very likely or somewhat likely to cure their cancer. Among patients who reported that a cure was very likely, there were more men (62%) compared to women (38%), more patients were aged less than 65 (62%) compared to over 65 (38%) and more patients had only completed elementary school level education (71%) compared to university level education (29%). Most patients (84%) felt treatment was either very likely or somewhat likely to help them live longer. 68% of patients felt treatment would help them with problems related to their cancer and 33% of patients felt that treatment was very likely to have side effects or complications. 22% of patients stated that doctors made decisions without their input. Conclusions: Many patients receiving treatment for incurable cancers do not understand that it is unlikely to be curative. Male gender, younger age and a lower level of education appears to be associated with unrealistic expectations. This could compromise their ability to make informed treatment decisions. More effective communication around goals of treatment and end of life care may help to improve patients understanding and expectations around the outcomes of chemotherapy.

179 Background: Combinative inhibitors with multiple actions to target downstream effectors are good strategy to reduce resistance occurrence. This is a preclinical study to evaluate efficacy of Palbociclib (P; CDK4/6 inhibitor) in combination with either Gedatolisib (G; P13K/mTOR dual inhibitors) or PD0325901 (PD; MEK 1/2 inhibitor) in CRC cell models. Methods: Five CRC cell lines with hot-spots mutations in PI3K and MAPK pathways genes are used. Cell growth assay is used to evaluate antiproliferative response to P, G and PD alone and in combination. RPPA is used to clarify the role actions of combinative drugs on resistance development and new druggable proteins. Paired t-test is used. Results: All cell lines except LS1034 (IC50=7.2µM) were sensitive to G. LS411N and SNUC4 were sensitive to P whereas Caco2, DLD1 and LS1034 were resistant (IC50>15µM). All cells lines were sensitive to PD. When tested in combination, P+G has synergistic response in all cells lines, except for LS411N (CI=0.9; p=0.02). P+G is highly synergistic in LS1034 with KRAS mutation (CI=0.1; p=0.11). P+G is also synergistic in DLD1 with co-occurring PIK3CA and KRAS mutations (CI=0.6; p=0.04). P+PD is synergistic in all cells lines except for LS411N. In SNUC4 with PIK3CA mutation, both drug combinations have equal synergism (CI=0.5; p [Table: see text]

1036Background: PI3K pathway activation is implicated in resistance to trastuzumab (T) therapy in breast cancer (BC). Copanlisib (C) is a pan-class I PI3K inhibitor with particular activity against...

e18910Background: FDA approval for bevacizumab (BEV) in progressive glioblastoma (GBM) was based on two phase II studies, both of which used a 10mg/kg every 2 weeks regimen. However, other studies ...

e15584Background: Chemotherapy combined with the angiogenesis inhibitor bevacizumab (bvz) is approved as a first-line treatment in the setting of metastatic Colorectal Cancer (mCRC) since 2004, but...

Purpose Squamous cell carcinoma (SCC) of the breast is rare and generally aggressive. In this study, we analyzed 33 patients treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) and a series of 137 patients identified through the Surveillance, Epidemiology, and End Results (SEER) database to make therapy recommendations. Methods Records of The University of Texas M.D. Anderson Cancer Center were searched for patients diagnosed with breast SCC from 1985 to 2001. All biopsy material was reviewed by a dedicated breast pathologist who performed immunohistochemistry for hormone receptors and the epidermal growth factor receptor (EGFR). We searched the SEER database for patients with breast SCC diagnosed between 1988 and 2001. Results We identified 33 patients with breast SCC, of whom two patients had metastatic disease at diagnosis. The median relapse-free survival (RFS) of 31 patients with localized disease was 20 months (range, 1 to 108 months), with a 26% RFS rate at 5 years. The median overall survival in these patients was 37 months (range, 12 to 108 months), with 40% surviving at 5 years. Median survival from the time recurrent disease was recognized was 14 months (range, 2 to 86 months). Tumors were usually hormone receptor–and HER2/neu-negative, though EGFR was frequently overexpressed. Information from the SEER database was consistent with most of our findings. Conclusion SCC of the breast is aggressive and often treatment-refractory. The role of platinum salts, EGFR inhibitors, and other novel agents needs to be explored.

3616 Background: Locally advanced rectal cancer, LARC (T3/4 and/or N+) is currently treated with neoadjuvant chemoradiotherapy (NACRT), however clinicopathological response is variable. Monitoring clonal evolution in response to NACRT may identify mutations driving therapeutic resistance or tumor growth after treatment. Methods: Fresh-frozen pre- and post-NACRT tumor and matched normal tissue from LARC patients were stratified into good (RCPath A), intermediate (RCPath B) and poor (RCPath C) responders. Following histological review, targeted exome capture was performed using an Agilent SureSelect Human all Exome V3 kit. Samples were sequenced to a minimum of 100X coverage on an Illumina HiSeq2000, and clonal evolution was assessed in matched pre- and post-NACRT tumor samples. Results: The median somatic mutation burden in pre-treatment samples was 114 (IQR 19-207). Two tumors were microsatellite (MSI) unstable and had elevated mutational burdens. The least evolution occurred in the poor responders, where there was little change in clonal composition after treatment, and driver mutations in genes including TP53 and APC were retained. On average 79% of pre-treatment mutations were retained post-treatment in poor responders and 33% of mutations were retained in intermediate responders. Many of the intermediate responders had loss of driver mutations including TP53 from the pre-treatment sample, but also shared a number of mutations in genes including PIK3CA and BRAF between pre- and post-treatment samples. There was also increased frequency in the post-treatment samples of clones that were not present in the pre-treatment samples. In one intermediate responder, all 47 mutations that were present in the pre-treatment sample including the driver mutations TP53 and APC were absent in the post-treatment sample, while 10 completely new mutations were identified. Conclusions: Dynamic mutational processes occur in LARC following selective pressures of exposure to NACRT, including changes in somatic mutation presence or frequency after treatment, owing to persistence or loss of sub-clones. As NACRT can profoundly affect the LARC genome, monitoring molecular changes during treatment may be clinically useful.

583 Background: In the TCHL trial (NCT01485926) 78 women with HER2-positive breast cancer (BC) underwent neo-adjuvant treatment with either TCH (Docetaxel, Carboplatin, Trastuzumab) or TCHL (TCH + Lapatinib) therapy. Of the 78 patients, 24 consented to an optional on-treatment biopsy 20 days after 1 cycle of therapy. We analysed the impact of tumour infiltrating lymphocytes (TILs) on pathological complete response (pCR) and also determined the impact of TCH/TCHL therapy on immune cell modulation after 20 days of treatment. Methods: We assessed TIL and stromal lymphocytes (SL) counts using immunohistochemical staining with Haemotoxalyin+Eosin, AE1/AE3 and CD45 in formalin fixed paraffin embedded (FFPE) baseline biopsy samples and in fresh frozen (FF) biopsies taken 20-days post cycle 1 (Day-20) of TCH/TCHL. RNA libraries were generated, using the Truseq mRNA library prep kit on the Neoprep platform and sequenced on the NextSeq 500. We measured the transcriptomic profile of 8 pre and on-treatment sample pairs and then used the Microenvironment Cell Populations (MCP)-counter method to measure the abundance of 10 immune cell populations (T cells, CD8 T cells, cytotoxic lymphocytes, NK cells, B lineage, myeloid dendritic cells, neutrophils, endothelial cells and fibroblasts). Results: We found that higher baseline levels of TILs (p = 0.045) but not SL were associated with an increased likelihood of a patient achieving a pCR to TCH/L based therapy. We found in day 20 on-treatment biopsies of women that subsequently went onto have a pCR that levels of SLs but not TILs were significantly higher (p = 0.049) than in those women who did not have a pCR. Finally we found significant increases in the level of monocytes (p = 0.05) and fibroblasts (p = 0.01), but not other immune cell populations, in the day 20 on-treatment biopsies in comparison with the mutated pre-treatment biopsies. Conclusions: In our study baseline TILs but not SLs have a predictive role in the likelihood of a patient achieving a pCR. We also found that TCHL based therapy significantly altered both monocytes and fibroblasts, indicating a possible role for these immune subtypes in response to TCHL therapy.

e13515 Background: Bevacizumab (BEV) has demonstrated activity in GBM, but the benefits have not been clearly defined in prospective randomised phase III trials. Some patients continue BEV for extended periods but little is known about predictors of clinical benefit. It has been suggested that a less intensive dose schedule might offer similar benefits. Methods: In a retrospective analysis of a National Neuro-Oncology centre database we examined biomarkers of BEV benefit on overall survival (OS), including age at diagnosis, time from diagnosis to BEV start, MGMT methylation and IDH-1 status. We compared those who derived clinical benefit (OS of ≥6-months) to those with limited clinical benefit (OS st 2010 and Dec 31st 2016, 170 patients received BEV for progressive GBM. Median OS was 5.5 months (Range: 0.5-54). OS was 42%, 18% and 2% at 6-, 12- and 24-months, respectively. No significant predictors of clinical benefit were identified (table). Importantly, median OS was similar for patients who received standard (N=94) vs. reduced intensity (N=76) BEV (5.2 vs. 5.6mo respectively), p=0.74. Conclusions: In this large cohort of patients, we did not identify predictors of benefit from BEV. OS was similar in patients who received standard or reduced intensity BEV. Given the cost of BEV, these results have important implications for value in cancer care. [Table: see text]

9032 Background: The EGFR-T790M somatic mutation is the most common mechanism of resistance to Tyrosine Kinase Inhibitors (TKI) in NSCLC. However patients with advanced disease are not always amenable to repeat biopsy for further molecular analysis. Developing non-invasive methods to detect T790M in cell-free DNA (cfDNA), in the absence of tissue is being actively investigated. Furthermore these 'liquid biopsies' may also overcome the problem of tumour genomic heterogeneity. Unfortunately the sensitivity of plasma for T790M detection has been disappointing with a significant chance of a false negative result. Exhaled breath condensate (EBC) is an easily collected sample and is known to harbour cfDNA, including lung cancer mutations. We explored the potential of EBC as a novel method of T790M detection. Methods: We recruited 26 patients who were either 1) known T790M positive pre/during Osimertinib therapy or 2) other mEGFR positive patients on 1st/2nd generation TKI. We collected matched plasma and EBC samples in the majority of cases. EBC samples were collected using the RTube device. Plasma was collected using standard EDTA tubes and extracted within 90 minutes. Using UltraSEEK chemistry, a targeted PCR for ultra-sensitive somatic mutation profiling on the MassARRAY system (Agena Bioscience), we compared the performance of EBC to plasma for the detection of T790M. Results: See Table. Conclusions: In this pilot study we describe the first ever report of the successful and consistent detection of T790M in the EBC of patients with EGFR mutated NSCLC, using a commercially available targeted assay. Our results suggest EBC is responsive to recognised dynamic molecular changes that occur on TKI treatment. We believe this makes EBC analysis an attractive avenue for future research, to optimise the detection of T790M mutations in liquid biopsies. [Table: see text]

11587 Background: The advent of immunotherapy represents a paradigm shift in the treatment of NSCLC compared to conventional chemotherapy. Recent studies have shown higher mts burden assessed by exome sequencing are associated with improved objective response and clinical benefit. We performed this study to evaluate the impact of ML assessment by LTP, correlating with PD-L1 exp and clinicopathological variables in resected NSCLC. Methods: NSCLC patients(pts) who underwent curative resection between 1998 and 2006 at our institution were included. PD-L1 status was assessed using Ventana SP124 antibody on archival FFPE surgical tumour specimens cores. PD-L1 was scored positive if membranous staining was present in >1% of tumour cells aggregated across the replicate cores to address heterogeneity. In collaboration with the Lung Cancer Genomics Ireland Study a targeted panel of 49 genes were assessed by Sequenom MassArray including genes in MAPK and PI3K pathways. Clinical data was obtained from hospital electronic database. Results: Ninety-one pts were included, of which 51 (56.0%) were males, with a median age of 65 years (range: 42 – 82). 51.6%, n=47 with squamous histological subtypes, 46.2%, n=42 were ex-smoker and 49.5%, n=45 had Stage I disease. 23.1%, n=21 had PD-L1 positivity. 149 mts were identified of which, 32(21.5%) with PHLPP2, 31(20.9%) with PIK3R1 and 21(14.1%) with TP53. The presence of PI3K and TP53 mts are associated with positive PD-L1 status (see table). An inverse correlation of PD-L1 positivity with ML of (1 vs 2 vs 3: 53.8% vs 30.8% vs 15.4%) was noted. Conclusions: We did not identify higher PD-L1 exp with higher ML assessed by a LTP widely used in clincial practice. However, positive PD-L1 exp was correlated with PIK3R1 and TP53 mts , warranting further investigation as potential modulators or surrogates of positve PD-L1 expression. [Table: see text]

587Background: ‘TCHL’ an ICORG phase-II neo-adjuvant study in HER2+ve Breast cancer (BC) assessed the impact of TCH (Docetaxel, Carboplatin, Trastuzumab) versus TCHL (Docetaxel, Carboplatin, Trastu...

e15140Background: Locally advanced rectal cancer is treated with neoadjuvant chemoradiation, but biomarkers are lacking to predict response to this therapy. Neutrophil/lymphocyte ratio (NLR) and pl...

11592Background: Aberrant apoptosis is coupled with chemotherapy-resistance. Here, we applied a mathematical model of downstream apoptosis execution (APOPTO-CELL) and investigated its suitability a...

591Background: TCGA analysis revealed that somatic EGFR, ERBB2, ERBB3 and ERBB4 mutations (ERBB family mutations) occur alone or co-occur with somatic PIK3CA mutations in 19% of HER2-positive breas...

554 Background: Sunitinib is a receptor tyrosine kinase inhibitor that has proven activity as first line treatment for metastatic renal cell carcinoma (mRCC). The recommended dose is 50mg once daily in a 4 week on 2 week off schedule. However this regimen has a significant side effect profile and alternative schedules have been used to minimize dose reductions and maintain dose intensity. We sought to identify the incidence of dose modifications and assess toxicity in patients treated with two sunitinib schedules in a National Cancer Center. Methods: Patients with mRCC who had sunitinib as first line treatment were identified retrospectively and patient data reviewed. Two patient groups were identified: those who received sunitinib 50mg day 1-28 in 6 week cycles (cohort 1) and those who received sunitinib 50mg day 1-14 in 3 week cycles (cohort 2). Primary end point was incidence of dose modification. Secondary end points included incidence of common sunitinib-related side effects. Known prognostic variables, including prior nephrectomy, body mass index (BMI) and use of angiotensin system inhibitors (ASI) were correlated with time to disease progression (TTP). Results: Between 2009 and 2014, 28 patients were identified. Of those, 23 (83%) patients were treated in cohort 1, and 5 (17%) patients in cohort 2. Dose modifications were required in 13 (56.5%) patients in cohort 1, but only 2 (40%) patients in cohort 2. Common sunitinib-related side effects in cohort 1 included hypertension in 19 (79%), weight loss in 10 (41.6%), fatigue in 9 (37.5%) and nausea in 8 (33.3%) patients respectively. Overall, the use of ASIs correlated significantly with longer median TTP (10.5 months) compared to non-users (4 months) (p = 0.04). BMI ≥ 25 (TTP 9 vs. 3 months, p = 0.008) demonstrated a similar correlation. However, no difference in median TTP was noted between patients who had prior nephrectomy compared to those who had not (5 vs. 4 months) (p = 0.18). Conclusions: In this small retrospective study, standard sunitinib scheduling was associated with a high incidence of dose modifications and side-effects. Consistent with previous studies, we identified known prognostic variables. The use of sunitinib 50mg day 1-14 in 3 week cycles may be more tolerable for patients.

1018 Background: The HRD-LOH (loss of heterozygosity) score is significantly associated with favorable response to neoadjuvant platinum-based therapy in PrECOG 0105. We set out here to assess the c...

11078 Background: Targeting oncogenic drivers has transformed the care of lung adenocarcinoma. However, there is no approved targeted therapy for lung SCC. LCGI aims to identify potential targets i...

5526 Background: BRCA1/2 mutations render ovarian cancers (OC) homologous recombination deficient (HRD) and thus sensitive to platinum and PARP inhibitors. Data on BRCA1 promoter methylation in OC,...

516 Background: PIK3CA mutations (mt) are frequently observed in BC but their clinical relevance is unclear. We performed an individual pt data pooled-analysis to evaluate the prognostic impact of ...

11077 Background: PTPN11/Shp2 somatic mutations occur in 25% of Juvenile myelomonocytic leukemias (JMML) and less commonly in adult solid tumors. PTPN11/Shp2 activates the mitogen-activated protein...

e17682 Background: To assess effect of chemotherapy on ovarian function (defined as regular menses plus at least 1 hormone within premenopausal range) in premenopausal BC after follow up 24-month p...

620 Background: Afatinib is a potent irreversible ErbB family tyrosine kinase inhibitor. We have previously shown that afatinib has anti-proliferative activity in a panel of 8 HER2 positive breast ...

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 (

e22174 Background: In contrast to lung adenocarcinoma, there are no known targetable oncogenes in lung SQCC. Herein, we thus screened for mutations in 49 kinome-related genes in lung cancer includi...

e13022 Background: ACTH-producing pituitary carcinomas (APPC) are malignant neuroendocrine tumors affecting the adenohypophysis. They are extremely rare, with a poor prognosis. They are poorly responsive to chemotherapy and radiotherapy. We report the case of a 25 year old female with a diagnosis of APPC, metastatic to bone, treated with temozolamide, followed by bevacizumab and the novel agent, pasireotide. Methods: The patient was diagnosed in 2002 with an ACTH-secreting pituitary macroadenoma causing Cushing’s disease. Despite two transphenoidal surgeries, bilateral adrenalectomies, craniotomy with excision of pituitary fossa tumour and radiotherapy she developed aggressive Nelson’s Syndrome. Following discontinuation of a somatostatin analogue in 2009 her ACTH levels rose dramatically causing progressive skin hyperpigmentation. Her disease continued to progress despite CyberKnife treatment. She was referred for temozolamide chemotherapy for treatment of the pituitary adenoma. At review, she had severe back pain. Investigations suggested metastatic disease and biopsy confirmed a diagnosis of metastatic APPC to bone.We commenced treatment with Temozolamide, however her disease progressed – ACTH levels were >200,000pmol/l in June 2012. Molecular profiling completed on the patient’s tissue was negative. Pasireotide, a novel multi-somatostatin receptor analogue, was commenced concomitantly with the anti-angiogenesis agent bevacizumab. Results: Treatment response is being assessed with imaging, serial monitoring of serum ACTH levels and skin examination. Interval imaging has shown stable disease, ACTH levels have decreased to 113,000pg/ml. Conclusions: Pituitary carcinomas are extremely rare representing 0.1-0.2% of pituitary neoplasms. To date, there is no established standard treatment, although there are reports of response to temozolamide.Our patient exhibited a clinical improvement and a reduction in ACTH levels after 6 months of combination therapy with pasireotide and bevacizumab. This combination is a possible therapeutic option in patients with metastatic ACTH-producing pituitary carcinoma.

3549 Background: Locally advanced rectal cancer, LARC (T3/4 and/or N+) is currently treated with pre-operative chemoradiotherapy (pCRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP-kinase (MAPK) and related pathways have been implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic variations in these pathways and clinical outcomes in LARC. Methods: We genotyped a total of 234 Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations in 33 cancer related genes including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET and NRAS using the Sequenom platform. DNA samples utilized herein were extracted from pre-treatment rectal cancer biopsies of 201 patients who were then treated with long-course pCRT followed by surgical resection. Results: 62 different mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (n=93, 47%), PIK3CA (n=29, 14%), MET (n=27, 13%), STK11 (n=13, 6.3%), CTNNB1 (n=12, 6%), BRAF (n=8, 4%) and NRAS (n=7, 3.5%). Mutations were also detected in AKT, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK and TNK2, but at frequencies of less than 2%. Pathologic complete response (pCR) was associated with excellent (97%) 5-year Recurrence-Free Survival (RFS) (Hazard ratio [HR], 0.076; 95% CI, 0.01-0.50, P=0.001). We found: 1) Mutations in PI3K pathway-related genes (PIK3CA, AKT, STK11) were significantly associated with absence of pCR (odd ratio [OR], 5.40; 95% CI, 1.24-23.54, P=0.024). However, mutations in MAPK pathway-related genes (KRAS, BRAF, NRAS, MEK) was not found to be significantly associated with pCR (P=0.805). 2) In contrast, in patients who did not achieve pCR (non-pCR), mutations in PI3K pathway-related genes were not associated with RFS. However, in these patients, codon 12 (G12D/G12V/G12S) and 13 mutations in KRAS were associated with poor RFS (HR, 0.336; 95% CI, 0.115-0.981, P=0.046). Conclusions: These results suggest that mutations in kinase signaling pathways may modulate treatment responsiveness and clinical outcomes in locally advanced rectal cancer and thus may constitute rational targets for novel therapies.

672 Background: Sensory neurotoxicity is a dose limiting side effect of oxaliplatin. The postulated cause is interference with ionic channels. Calcium and magnesium pre and post oxaliplatin infusion have been suggested to prevent this as they act as chelators. Methods: We performed a review of all patients who were treated with oxaliplatin over a 2 year period. 25 patients received oxaliplatin with calcium gluconate 1g and magnesium sulphate 1g (Ca/Mg group) and 33 did not (no Ca/Mg group). 49 (84%) patients received oxaliplatin as part of the FOLFOX regimen. Other regimens included XELOX, EOX and FLOX. Peripheral neuropathy was defined and graded by the Common Terminology Criteria for Adverse Events v3.0 and was assessed by a clinical nurse specialist (CG). Results: 55 (95%) patients had peripheral neuropathy. There was no significant difference in overall neuropathy and the grade of neuropathy between the Ca/Mg group and no Ca/Mg group. 4 patients required discontinuation of oxaliplatin. One patient (Ca/Mg group) required dose reduction. Patients requiring medical treatment were treated with pregabalin. Conclusions: Oxaliplatin-induced neuropathy is a drug limiting adverse effect. We found that the addition of calcium gluconate and magnesium sulphate did not reduce the incidence or severity of peripheral neuropathy experienced in our cohort. It has been suggested (Park S.B. et al. The Oncologist. 2011;16:708-716) that oxaliplatin induced peripheral neuropathy may not be reversible. This emphasises the importance of managing this difficult symptom appropriately. [Table: see text]

2558 Background: SF1126 is composed of the pan PI3K inhibitor LY294002 conjugated to an RGD targeting peptide. It is designed to increased solubility and binding to integrins expressed on tumor vasculature. This targeted prodrug enhances tumor delivery of the active inhibitor, improving antitumor efficacy and tolerability in xenograft models. LY294002 inhibits other kinases including mTOR, DNA-PK, PIM1, PLK1, and CK2, and induces oxidative stress in cancer cells independent of its PI3K inhibition. Methods: Pts with advanced solid tumors are enrolled in sequential cohorts in standard 3+3 design. SF1126 is administered days 1, 4 weekly by 90 minute IV infusion in cycles of 4 weeks. Pharmacodynamic (PD) evaluations of PI3K pathways are being measured in PBMC, skin/hair and tumor samples as well as by 18FDG PET scans. Primary objectives are safety, establish MTD and recommended phase 2 dose. Results: 28 pts have been treated with SF1126126 across 7 dose levels of 90, 140, 180, 240, 320, 430, and 630 mg/m2. One dose limiting toxicity (DLT) was seen at the 180 mg/m2 dose, consisting of transient G3 diarrhea. No other grade 3/4 drug related toxicities have been reported. No consistent effects on blood glucose levels noted. Eleven pts showed stable disease for ≥ 8 wks, including durations of 20 wks for one GIST, 1 endometrial, and 1 prostate; 15 wks for 1 pancreatic; 11 wks for 2 GIST, 2 ovarian, and 1 CRC pt. PK: SF1126 is rapidly cleared after infusion termination. PK of active hydrolysis product (LY294002) shows t1/2 ∼1.6–2 hrs; dose proportional Cmax, achieving ∼ 21uM at 630 mg/m2; and AUC(0-t) nearly dose proportional. Mean AUC values at doses ≥ 140 mg/m2 exceed those found effective in mouse xenograft studies. PD: Compared to baseline biopsy, we observed significant inhibition of pS6 by IHC in a tumor biopsy 20 hours after the 8th dose in a pancreatic cancer pt at 240 mg/m2. Conclusions: SF1126 is well tolerated at doses up to 630 mg/m2 given twice weekly. MTD has not been reached; dose escalation continues. Clinical activity includes disease stabilization in multiple pts with refractory tumors. There is early evidence of target pathway inhibition. [Table: see text]

5536 Background: The objective of this study was to evaluate survival over time in relation to FDA approval of paclitaxel (P) for second- and first-line treatment in a population-based cohort of women with stage III and de novo stage IV ovarian cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) program was searched to identify 8,267 and 10,746 women with stage III and stage IV epithelial ovarian cancer diagnosed between 1988–2004. Women were divided according to their year of diagnosis and year of FDA approval of P for second- (1992) and first-line(1998) treatment of ovarian cancer: Group1 (1988–1991; before P approval); Group2 (1992–1997; P approved for second-line); Group3 (1998–2003; P approved for first-line). Overall (OS) and ovarian-cancer-specific survival (OCS) were estimated using Kaplan-Meier product method and compared across groups with log rank statistic. Cox-proportional hazards models were fitted to determine the association of group year of diagnosis and survival after adjusting for patient/tumor characteristics. Results: Median age was 66 years. Median OCS was 44 and 18 months among women with stages III and IV disease, respectively. With stage III disease, 2-year OCS was 64%, 68%, and 70% for groups 1, 2, and 3, respectively (p < 0.0001). With stage IV disease, 2-year OCS was 39%, 41%, and 42% for groups 1, 2, and 3, respectively (p = 0.19). In the multivariable model for stage III disease, women in group 1 (HR = 1.4, 95% CI 1.2–1.5, p < 0.0001) and group 2 (HR = 1.2, 95% CI 1.1–1.3, p = 0.0003) had an increased hazard of ovarian-cancer-specific death vs. group 3. For stage IV disease, women in group 1 (HR = 1.2, 95% CI 1.12–1.3, p < 0.0001) had a significantly increased hazard of ovarian cancer-specific death, but no significant difference in group 2 (HR = 1.0, 95% CI 0.9–1.1, p = 0.88) vs. group 3. Similar trends were observed for OS. Conclusions: The survival of women with stages III and IV ovarian cancer has significantly improved with the introduction of P over the last two decades. However, the incremental improvement in survival with stage IV disease is clinically minimal and indeed not significant in the univariable analysis in the SEER patient cohort analyzed, suggesting a desperate need for new and more active drugs in these patients. No significant financial relationships to disclose.

9554 Background: The purpose of this analysis is to describe the characteristics and clinical outcomes of female patients with primary breast angiosarcoma. Methods: The M. D. Anderson Cancer Center Breast Medical Oncology database was searched to identify breast angiosarcoma patients between 1965–2002. Survival outcomes were estimated by the Kaplan-Meier method. The log-rank statistic was used to compare groups. Cox proportional hazards models were used for multivariate analysis. Results: The 69 patients had a median follow up of 40 months (range, 0–413 months). Median age at diagnosis was 46. Median tumor size was 5.5 cm. Thirteen patients had received prior chest radiation (18.8%) for invasive breast carcinoma and were older than other patients (p No significant financial relationships to disclose.

656 Background: We aimed at determining the pathologic features of metastatic breast lesions to the brain, and their correlation with the primary tumor, and their effect on postneurosurgical survival (PNS). Methods: Tissue samples from 123 pts who underwent surgical resection of BM at MDACC between 1984–2004, were examined for estrogen receptor-α (ER) by IHC and HER2 by FISH or IHC. Pts’ medical records were retrospectively reviewed for CC. Results: Median (med) age at BM diagnosis was 51 years. The med time from primary diagnosis to BM was 33 months (Range (R)0–304). Infiltrating ductal cancers were found in 89%. ER was negative and HER2 amplified in 73% and 37% of BM, respectively; ER-/Her2- was seen in 43%, ER-/Her2+ in 30%, ER+/Her2+ in 6%. Concordance of ER and HER2 status between primary and BM were both 88% (p=NS, for discordance). ER positivity was associated with a longer primary diagnosis to BM interval [med 39 months (R, 0–213) vs. 29 months (R, 0–304) in the ER- pts; p=0.02]; HER2 amplification was not (p=0.82). The med PNS was 11.2 months (R, 9.0–13.5) for 112 pts with no pre- craniotomy brain radiation. Pts with ER+ metastases experienced apparent longer PNS survival than ER- pts [med 18.9 months (95% CI, 4.8–33.1) vs. 9.9 months (95% CI, 7.6–12.1 months), respectively, p=0.06], as did those with HER2-amplified BM [med 13.8 months vs. 9.9 months, respectively; p=0.10]. Pts aged 45 to No significant financial relationships to disclose.

4557 Background: The extent of neuroendocrine differentiation in prostate cancer correlates with aggressive disease and progression to hormone refractory prostate cancer (HRPC). Elevated plasma chromogranin A (CgA) levels in prostate cancer patients may reflect more extensive neuroendocrine phenotype. We therefore sought to test the hypothesis that CgA levels are of prognostic value in patients with HRPC. Methods: Pretreatment plasma was collected from 390 patients with metastatic HRPC enrolled in CALGB 9480, a study of 3 different dose levels of suramin. Plasma CgA levels were determined in 321 of the samples in duplicate using a quantitative sandwich immunoassay (DAKO Corp. Carpinteria, CA, Cat. No. K0025). The proportional hazards model was used to assess the prognostic significance of CgA in predicting overall survival. Results: Plasma CgA levels ranged from 7.7–19.3 U/L, with a median level of 12 U/L. In univariate analysis plasma CgA levels inversely correlated with survival times at the median CgA ...