Ashwin Reddy Sama

Clinicopathologic factors associated with lymph node retrieval in resectable colon cancer: A veterans' affairs central cancer registry (VACCR) database analysis

A long‐term determinant of survival in resectable colon cancer is the involvement of regional lymph nodes. We evaluated the clinicopathologic factors associated with lymph node retrieval.

A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone

Lessons Learned Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone. There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone. Background. We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone. Methods. This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1–7 every 21 days) per standard 3+3 design. Results. Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. Conclusion. A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.

Refractory fallopian tube carcinoma - current perspectives in pathogenesis and management

Fallopian tube carcinoma (FTC) is considered a rare malignancy, but recent evidence shows that its incidence may have been underestimated. Risk-reducing salpingo-oophorectomy (RRSO) in breast cancer susceptibility gene (BRCA)-positive women has provided a unique opportunity to study the pathogenesis of FTC and ovarian carcinomas. Newer data now suggest that most high-grade serous cancers of the ovary originate in the fimbrial end of the fallopian tube. Due to the presumed rarity of FTC, most current and more recent ovarian cancer clinical trials have now included patients with FTC. The treatment guidelines recommend similar overall management and that the same chemotherapy regimens be used for epithelial ovarian cancers and FTC.

Abstract C46: NSABP FC-7: A phase Ib study evaluating neratinib (N) and cetuximab (Cmab) in patients (pts) with quadruple wild-type (quad wt) (KRAS/NRAS/BRAF/PI3KCA wt) metastatic colorectal cancer (mCRC) resistant to Cmab

Background Multiple mechanisms may account for de novo and acquired resistance to Cmab. One mechanism, HER2 amplification, promotes heterodimer formation with HER3, bypassing EGFR blockade and resulting in downstream signaling. Bertotti reported HER2 amplification rates of 2.7% in unselected CRC pts (n = 2349), 13.6% in KRAS wt, Cmab-resistant pts (n = 44), and 36.4% in quad wt, Cmab-resistant xenopts (n = 11), suggesting that HER2 amplification is selected for by prior Cmab exposure. To test the hypothesis that dual ERBB blockade could overcome resistance to Cmab in quad wt mCRC pts, as suggested by preclinical data, we combined N, an oral small molecule tyrosine kinase inhibitor that irreversibly binds to pan ERBB receptor tyrosine kinases, with Cmab in mCRC pts who progressed on previous anti-EGFR therapy (tx). Methods In this phase Ib study, 15 anti-EGFR tx (Cmab or panitumumab [Pmab])-resistant pts with quad wt mCRC have been enrolled. Clinical endpoints included determination of safety and efficacy of the combination of Cmab, fixed dose 250 mg/m2 iv weekly, and N at escalating doses of 120, 160, 200, and 240 mg/d continuously using 3+3 design. Each cycle was 28 d. All eligible pts must have had prior tx with at least oxaliplatin, irinotecan, and Cmab or Pmab, are required to have archived tumor available before initial anti-EGFR tx with quad wt profile, and agree to a research biopsy at time of enrollment (after anti-EGFR progression), ECOG PS Findings The MTD of N in combination with Cmab has not been reached. Accrual to the final cohort 240 mg/d is ongoing. Of 14 pts evaluable for toxicity, 1 pt on N 240 mg/d experienced DLT of grade 3 diarrhea for ≥48h. One had grade 3 diarrhea at N 200 mg/d in cycle 3 for Conclusion Dual anti-ERBB therapy with Cmab and N was safe and well tolerated. Despite multiple prior therapies, SD was seen in 5 of 9 evaluable pts including 1 pt at N 120 mg/d. A trend toward longer duration of SD was observed in the pts who were HER2 pos. Four of 11 post-Cmab tissues (36%) were HER2 pos, including 3 who converted from HER2 neg to pos and 1 was pos pre-and post-Cmab. Support: Puma Biotechnology, Inc. Citation Format: Samuel A. Jacobs, James J. Lee, Thomas J. George, Jr., James L. Wade, III, Philip J. Stella, Ding Wang, Ashwin R. Sama, Marc E. Buyse, Jodi A. Kanyuch, Ashok Srinivasan, Kay L. Pogue-Geile, S. Rim Kim, Norman Wolmark, Carmen J. Allegra. NSABP FC-7: A phase Ib study evaluating neratinib (N) and cetuximab (Cmab) in patients (pts) with quadruple wild-type (quad wt) (KRAS/NRAS/BRAF/PI3KCA wt) metastatic colorectal cancer (mCRC) resistant to Cmab. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C46.

A case of periampullary adenocarcinoma in neurofibromatosis type 1

Neurofibromatosis type 1 (NF-1) is an autosomal dominant genetic disorder with a known predisposition to gastrointestinal neoplasms such as stromal tumors and carcinoids. Adenocarcinomas (ACs) of the gastrointestinal tract are relatively rare in patients with NF-1, especially those found in the periampullary region. We present a case report of periampullary adenocarcinoma in a 56-year-old woman with NF-1 who presented with abdominal pain and obstructive jaundice.

HER-2-Positive Ampullary Adenocarcinoma: A Case Report

Abstract Background: Ampullary adenocarcinomas are a rare subset of periampullary tumors with an overall poor prognosis. Treatment decisions are generally extrapolated from pancreatic chemotherapy protocols and consist mainly of traditional chemotherapy drugs. There are no known targets for therapeutic intervention in ampullary adenocarcinoma at this time. Next generation sequencing and other novel molecular profiling of tumors, including circulating tumor DNA (ctDNA), have recently made it possible to better understand tumor biology and elucidate driver mutations which are amenable to targeted therapy. This case describes the use of novel DNA sequencing technology to provide a targeted treatment option, HER-2 inhibition, in a patient with HER-2 overexpressing ampullary adenocarcinoma. This is the first time this has been described in the literature. Case presentation: The patient is a 63-year-old Caucasian man who initially presented with symptoms of obstructive jaundice and was found to have a periampullary tumor. He underwent resection of his tumor and pathology confirmed a stage IIB ampullary adenocarcinoma. He unfortunately developed a recurrence in the liver and lung two years later. Next generation sequencing of his tumor at the time of resection as well as ctDNA analysis demonstrated a HER-2 overexpressing tumor. Following first line therapy with FOLFOX he had progression and was treated with trastuzumab and pertuzumab with stabilization of his disease prior to his ultimate demise from multifocal pneumonia. Conclusion: The use of next generation sequencing as well as ctDNA technology generated a novel therapeutic intervention in our patient. As these techniques become more widespread, it is likely more targeted therapies will be used in these difficult to treat diseases.

Molecular Profiling of Synchronous Colon Cancers and Anaplastic Thyroid Cancer in a Patient with Lynch Syndrome

Lynch syndrome is an autosomal dominant cancer susceptibility disorder caused by either a germ line mutation in a DNA mismatch repair gene: MLH1, MSH2, MSH6, or PMS2 or deletion of the last few exons of the EPCAM gene leading to epigenetic silencing of MSH2 [1]. The deficient mismatch repair leads to a hyper mutated state as exemplified by microsatellite instability and eventual carcinogenesis. Clinically, the hallmark of Lynch syndrome is an increased predisposition to the development of colorectal cancers at a significantly younger age relative to their sporadic counterparts, metachronous and synchronous colonic primaries [1]. An increased frequency of neoplasia is also observed in the endometrium, ovary, upper urinary tract, stomach, hepatobiliary, pancreas, small intestine, brain/CNS, sebaceous glands, and keratoacanthomas [1]. Notably,MSH6mutations are associated with a higher proportion of extracolonic neoplasms, a later age of onset of these cancers, and a slightly lower risk of colorectal cancer [2, 3]. Thyroid carcinomas are not traditionally considered to be a part of the Lynch syndrome spectrum, and only two reports describe Lynch patients with thyroid cancer, both harboringMSH2 mutations and without synchronous colorectal carcinomas [4–6]. Recent data has linked tumors driven by microsatellite instability to response to immune-oncology approaches, such as anti-PD1 therapies [7, 8]. We describe here two synchronous colonic and an anaplastic thyroid carcinoma assessed by comprehensive genomic profiling (CGP) in the course of clinical care to demonstrate a hypermutated state thus presenting a potential therapeutic option for this unique clinical presentation.

SU-E-T-131: Artificial Neural Networks Applied to Overall Survival Prediction for Patients with Periampullary Carcinoma

Purpose: Artificial neural networks (ANN) can be used to discover complex relations within datasets to help with medical decision making. This study aimed to develop an ANN method to predict two-year overall survival of patients with peri-ampullary cancer (PAC) following resection. Methods: Data were collected from 334 patients with PAC following resection treated in our institutional pancreatic tumor registry between 2006 and 2012. The dataset contains 14 variables including age, gender, T-stage, tumor differentiation, positive-lymph-node ratio, positive resection margins, chemotherapy, radiation therapy, and tumor histology.After censoring for two-year survival analysis, 309 patients were left, of which 44 patients (∼15%) were randomly selected to form testing set. The remaining 265 cases were randomly divided into training set (211 cases, ∼80% of 265) and validation set (54 cases, ∼20% of 265) for 20 times to build 20 ANN models. Each ANN has one hidden layer with 5 units. The 20 ANN models were ranked according to their concordance index (c-index) of prediction on validation sets. To further improve prediction, the top 10% of ANN models were selected, and their outputs averaged for prediction on testing set. Results: By random division, 44 cases in testing set and the remaining 265 cases have approximately equal two-year survival rates, 36.4% and 35.5% respectively. The 20 ANN models, which were trained and validated on the 265 cases, yielded mean c-indexes as 0.59 and 0.63 on validation sets and the testing set, respectively. C-index was 0.72 when the two best ANN models (top 10%) were used in prediction on testing set. The c-index of Cox regression analysis was 0.63. Conclusion: ANN improved survival prediction for patients with PAC. More patient data and further analysis of additional factors may be needed for a more robust model, which will help guide physicians in providing optimal post-operative care. This project was supported by PA CURE Grant.

Clinicopathologic features and survival outcomes of primary signet ring cell carcinoma of colon: Retrospective analysis of VACCR database.

e14097 Background: Signet ring cell carcinoma accounts for less than 1% of all colon cancers. We examined the clinical pathological features and prognosis of signet ring cell carcinoma of colon Methods: A total of 206 patients diagnosed with signet ring cell carcinoma from 1995 to 2009 were identified from the VA Central Cancer Registry (VACCR) database. Age, race, histology, grade, lymph node status, stage and type of treatment received data were collected. RESULTS Out of 206 patients, 173 (83.9%) were white, 31 (15%) were black, and 2 patients were listed as unknown. Median age of diagnosis was 67 years as compared to 70 years for both mucinous and non-mucinous adenocarcinoma of colon. Pathological T-stages were as follows: T1 = 2.9%, T2=5.3%, T3=33.9%, T4= 25.7%, and unknown 32%. Of the total, 22.3% were located in caecum, 21.8% in ascending colon, 15.5% in sigmoid colon, 7.7% in appendix and hepatic flexure of colon, 11.1% in transverse colon, 2.9% in splenic flexure and 4.4% in descending colon. 33.5% were lymph node positive, 34.6% were lymph node negative, and 31.8% were unknown. Histological grade 3-(55.4%) was most commonly reported followed by grade 2 (7.3%), grade1 (2.5%), grade 4 (1.9%) and in 33% grade was unknown. 41.3% patients received only surgery while 34% received surgery with adjuvant chemotherapy, 7.3% received chemotherapy alone, 7.8% received radiation alone and 9% did not receive any therapy. 1 yr, 3 yr and 5 yr survivals for signet ring cell cancer compared to adeno carcinoma was 60% vs 80%, 33% vs 60%, and 24% vs 47% respectively. Median survival of signet ring cell carcinoma compared to mucinous and non mucinous adenocarcinoma was 19 mos, 48 mos and 67 mos respectively. CONCLUSIONS Signet ring cell carcinoma of colon has poor survival rates than other histological subtypes. Signet ring cell carcinoma presents at an earlier age, has higher tumor grade and advanced stage at diagnosis when compared to mucinous and non-mucinous adeno carcinoma of colon. Due to rarity of this disease further multi-institute studies are required for in-depth understanding of this disease.