Abstract Introduction: The outcome of patients with metastatic colorectal carcinoma (mCRC) following first line therapy, especially with a K-ras mutation is poor with median survival of less than one year. The purpose of this study was to perform whole genome sequencing (WGS) to identify therapeutically actionable somatic events in mCRC patient samples, so as to select targeted treatment strategies for individual patients. Methods: IRB approval was obtained and 3 patients have been enrolled. All had > 2 prior regimens and had known K-ras mutations (age 73, 45 and 50 years, all were male). Percutaneous needle biopsies of liver metastases were performed with whole blood collection for the extraction of constitutional DNA. WGS was performed using Illumina paired end chemistry on HiSeq2000 sequencing system, which yielded coverage of greater than 30X for both the normal and tumor samples. Somatic genomic alterations (point mutations and indels, copy number alterations, translocations and rearrangements) were analyzed using our custom pipeline for paired analysis. Results: In all 3 samples sufficient DNA was extracted for sequencing. WGS and bioinformatics analysis took 3–4 weeks for completion. We found that all 3 tumor samples had KRAS mutations, while 2 samples had mutations in the APC gene and the PIK3CA gene. Other genes with therapeutic implications in single tumor samples were INPPL1, INPP4B and SMAD4. No EGFR amplifications were detected in our sample set. The concomitant mutations in MAPK (K-ras) and PI3K (PIK3CA, INPPL1, INPP4B) pathways suggest that combination therapies might be required for effective treatment of these tumors. In two instances, tumors were sent to a CLIA laboratory to allow for clinical validation of genomic events. Conclusions: WGS is feasible from DNA obtained from percutaneous biopsies in a clinical setting. Our study has revealed a series of therapeutically actionable events in mCRC and prospective clinical trials are needed to validate this approach. Funded by the Bisgrove-Scottsdale Healthcare and TGEN foundations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A183.
Anaplastic pancreatic carcinoma is an aggressive neoplasm with survival measurable in weeks. It presents as a large cystic mass with loco-regional and distant spread. Three histological types have been described: pleomorphic, spindle cell and sarcomatoid.We describe the case of a 74-year-old woman with pleomorphic anaplastic carcinoma of the pancreas diagnosed after laparoscopic biopsy. The patient had a rapid downhill course with progression of the disease and demise within 4 weeks after diagnostic laparoscopy.Due to the rapid spread of the disease, no effective cure exists for these tumors. A brief review of the histological and radiological findings and the possible mechanisms of the pathogenesis of anaplastic tumors is included in the discussion.
9578 Background: Fewer than 20% of patients (pts) with pancreatic cancer survive 5 years following pancreatico-duodenectomy. Limited data exist regarding downstream activation of EGFR signaling in pancreatic carcinoma. We investigated expression of EGFR, MAPK (ERK-MAPK), AKT, and their phosphoforms (p-) and correlated these with clinical outcome. Methods: Clinical data of forty-three consecutive cases of pancreatic carcinoma who underwent pancreatico-duodenectomy were obtained. Immunohistochemical staining of paraffin embedded blocks was performed using monoclonal antibodies against EGFR, MAPK, p-MAPK, AKT and p-AKT. Standard immunoperoxidase technique was used to detect the avidin- biotin peroxidase complex. Protein expression was visually scored using histoscore method, independently by two pathologists. Results: Forty-two pts underwent pancreatico-duodenectomy. Pts characteristics: sex-21 men, 22 women; median age- 66 years (range: 32 to 84); TNM Stage I-3 pts, Stage II/III-34 pts and Stage IV-6 pts. Tumor was grade 1 in 4, grade 2 in 20 and grade 3 in 18 cases. Additional therapies were chemotherapy (n=5), radiotherapy (n=1) and combined chemo-radiotherapy (n=19). Immunohistochemistry revealed increased expression of EGFR in 27.9%, MAPK in 89.5%, p-MAPK in 26.8%, AKT in 39.5% and p-AKT in 13.9% of cases. The cumulative logit model showed that EGFR expression correlated with high tumor grade (OR=6.7, p=0.0101). Data analysis using Kaplan-Meier method and log rank test revealed that high p-MAPK expression (n=14) correlated with shorter median survival (10 months) than low expression (n=26, 21 months, p=0.0049). High expression of p-AKT (n=21) was associated with longer median survival (24 months) than low expression (n=21. 9 months, p=0.0025). Multivariate analysis using the Cox-proportional hazard model identified age (HR = 1.13, p=0.0005), p-AKT (HR=0.05, p=0.0005) and p-MAPK (HR=7.94, p=0.0011) as predictors of survival. Conclusions: EGFR and its downstream proteins are often activated in pancreatic carcinoma. Expression of p-MAPK, advanced age and high tumor grade are associated with poor survival after pancreatico-duodenectomy. Supported by NIH grants CA62502 and CA16056. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Genentech, Roche
Long-acting sandostatin (S-LAR; octreotide acetate) is well tolerated and effective for symptom control and possibly disease control in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We undertook a retrospective analysis to study the efficacy and tolerability of higher doses (more than 20-30 mg/month) of S-LAR in GEP-NETs.With IRB approval, charts of all patients with GEP-NET who received S-LAR between June 2002 to September 2007 at Roswell Park Cancer Institute were reviewed and their data analyzed.Fifty-four patients with GEP-NET received S-LAR; thirty required dose escalation. Patients received a median of 5 doses of S-LAR at conventional dose followed by up-titration of the dose for symptom control (20) and radiological progression (17). Median high dose of S-LAR was 40 mg (range: 40-90 mg) with a median of 8.5 high doses received. No treatment related toxicities were seen. The estimated 1-year survival for patients on conventional dose alone was 0.77 (95% CI of 0.50 to 0.91) and those on high-dose was 0.88 (95% CI of 0.68 to 0.96) (p=0.4777) while median time to any other intervention was 2.9 months versus 17.7 months (p=0.12).Dose escalation of S-LAR is well tolerated and may provide longer disease control.
3060 Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated to an 18 aa cytolytic peptide. Selective targeting in LHRH-R expressing cells occurs via direct binding to the extracellular membrane receptor followed by disruption of the membrane by the cytolytic peptide portion. A first in human, phase I study was performed. Methods: Eligible pts had adequate organ function and LHRH-R tumor expression, as determined by IHC. EP-100 was given IV (30-60 min) weekly x 3 for cohorts 1- 6 (n=20 at 0.6 - 5.2 mg/m 2 ) and then twice weekly x 3 for cohorts 7- 11 (n=18 at 7.8 - 40 mg/m 2 ) with a week break. The pharmacokinetic profile of EP-100 and antibody production against EP-100 was determined by a validated HPLC/MS and ELISA respectively. Potential activity of EP-100 on the pituitary gonadotropes was determined by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37 were enrolled (female 76%) and treated. The LHRH-R expression rate in breast was 81% (N=21) and in ovarian cancer 56% (n=18). Most pts had breast (n= 16, 42%) ovary (n=7,18%), colon (n=4, 11%) or uterine (n=3, 8%) cancer. Pts were treated in a 3 + 3 standard dose escalation scheme. Doses were escalated 100% in the absence of a grade 2 drug related toxicity. MTD was not reached at the highest dose level of 40 mg/m 2 . Only one DLT occurred, a grade 2 increase in ALT/AST. The only other drug-related toxicity was a self limited infusion-related skin reaction (grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean half life ranged from 7.1 ± 3.8 min to 15.9 ± 3.6 min. Best response was stable disease for >12 weeks in 5 pts. In 3 pts rapid, sustained decreases in LH/FSH levels were noted. Antibody production against EP-100 was absent in all pts. Conclusions: The study has completed accrual, the phase II dose is 30-40 mg/m 2 twice a week x 3 weeks.EP-100is safe, well tolerated and not antigenic/immunogenic. Preclinical studies indicated synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus paclitaxel in ovarian cancer is planned.
Hepatocellular carcinoma (HCC) is primary hepatic malignancy with a high incidence of recurrence. The risk of recurrence directly correlates to patient's overall prognosis. Management of advanced HCC involves a combination of surgical resection, locoregional therapy, and systemic treatment. Distant metastases are rare, and intraventricular cardiac metastases are even more infrequent. This brief review details an illustrative case of cardiac metastasis after curative treatment of primary HCC and then summarizes the literature on risk factors, treatment options, and patient prognosis in the setting of distant metastases from HCC. Prognosis of metastasis to the heart is generally poor, and available evidence emphasizes the importance of maintaining regular posttreatment screening for metastases in patients with HCC. Given the variable presentation and high risk of recurrence, it is critical to have individualized multimodality treatment plans.
Abstract Antiandrogen withdrawal response is an increasingly recognized entity in patients with metastatic prostate cancer. To our knowledge, there have been no reports describing a durable radiologic improvement along with prostate-specific antigen (PSA) with discontinuation of the antiandrogen agent bicalutamide. We report a case in which a dramatic decline of serum PSA levels associated with a dramatic improvement in radiologic disease was achieved with bicalutamide discontinuation.
e20575 Background: Increasing epidemiologic data suggest association of vitamin D deficiency with influenza epidemic. Vitamin D acts as an immune modulator and stimulates the expression of protective anti-microbial peptides. We conducted a prospective influenza vaccination study to determine the influence of vitamin D status on serological response to flu vaccine in cancer patients. Methods: Cancer patients at Roswell Park Cancer Institute were offered trivalent (H1N1, H3N2, B/Malaysia) Flu vaccine (Fluzone, 2006–7) and sera collected for hemagglutination inhibition (HI) assay titers. Response to vaccination was defined as ≥ 1:40 titer ratio or a 4 fold increase in HI titer at 3 months post vaccination, against any of the 3 strains. Chi-square tests were performed to compare serological response between the groups with lowest and highest quartiles of baseline 25 (OH) vitamin D (D) level. Logistic regression model was used using other covariates such as age, gender, cancer type, and chemotherapy (CT) as controls. Results: 85 patients with colorectal, 35 with prostate, 1 with anal and 1 with gastric adenocarcinoma participated in the study. Median age was 62 years (range: 24–87 years), 85 (70%) were males. Overall serological response was 59%. Median baseline D level was 42.9 ng/mL (range: 4.0–92.8 ng/mL); lowest and highest quartiles were 26.9 and 53.4 ng/mL. There was no association between serological response and baseline D level (p=0.42) or the lowest and highest quartiles of D level (p=0.6). The odds of response did not vary by sex (p=0.95). CRC patients (OR-0.051; 95% CI-0.013 to 0.209; p<0.0001) were less likely to respond. Few patients (n=20; 16%) were D deficient (<20ng/mL), 43 had D < 32ng/mL .70 patients (54.7%) were on vitamin D supplements. Among those in whom the dose of supplement was known (46),the median daily vitamin D supplement dose was 2000 IU (800–9000 IU).There was no association between serological response and dose (p=0.09). There was no difference in the response rates among patients on D supplement 44/70 (62.9%) versus those not on any D supplement 28/52 (53.8%)(p=0.32). Conclusions: Vitamin D status, in a population in which vitamin D supplementation was commonly used, did not affect serological response to influenza vaccine. No significant financial relationships to disclose.
