Namrata Vijayvergia

Lifestyle Factors in Cancer Survivorship: Where We Are and Where We Are Headed.

Advances in early detection and curative therapies have led to an increased number of cancer survivors over the last twenty years. With this population comes the need to evaluate the late and long term effects of cancer treatment and develop recommendations about how to optimally care for these survivors. Lifestyle factors (diet, body weight, physical activity, and smoking) have been linked to a higher risk of many medical comorbidities (cardiovascular, metabolic, etc.). There is increasing evidence linking these factors to the risk of developing cancer and likely cancer-related outcomes. This link has been studied extensively in common cancers like breast, colon, prostate, and lung cancers through observational studies and is now being prospectively evaluated in interventional studies. Realizing that survivors are highly motivated to improve their overall health after a diagnosis of cancer, healthy lifestyle recommendations from oncology providers can serve as a strong tool to motivate survivors to adopt health behavior changes. Our article aims to review the evidence that links lifestyle factors to cancer outcomes and provides clinical recommendations for cancer survivors.

Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites

Metastatic colorectal cancer (mCRC) carries a poor prognosis with an overall 5-year survival of 13.1%. Therapies guided by tumor profiling have suggested benefit in advanced cancer. We used a multiplatform molecular profiling (MP) approach to identify key molecular changes that may provide therapeutic options not typically considered in mCRC. We evaluated 6892 mCRC referred to Caris Life Sciences by MP including sequencing (Sanger/NGS), immunohistochemistry (IHC) and in-situ hybridization (ISH). mCRC metastases to liver, brain, ovary or lung (n = 1507) showed differential expression of markers including high protein expression of TOPO1 (52%) and/or low RRM1 (57%), TS (71%) and MGMT (39%), suggesting possible benefit from irinotecan, gemcitabine, 5FU/capecitabine and temozolomide, respectively. Lung metastases harbored a higher Her2 protein expression than the primary colon tumors (4% vs. 1.8%, p = 0.028). Brain and lung metastases had higher KRAS mutations than other sites (65% vs 59% vs 47%, respectively, p = 0.07, <0.01), suggesting poor response to anti-EGFR therapies. BRAF-mutated CRC (n = 455) showed coincident high protein expression of RRM1 (56%), TS (53%) and low PDGFR (22%) as compared with BRAF wild-type tumors. KRAS-mutated mCRC had higher protein expression of c-MET (47% vs. 36%) and lower MGMT (56% vs. 63%), suggesting consideration of c-MET inhibitors and temozolomide. KRAS-mutated CRC had high TUBB3 (42% vs. 33%) and low Her2 by IHC (0.5%) and HER2 by FISH (3%, p <0.05). CRC primaries had a lower incidence of PIK3CA and BRAF mutations in rectal cancer versus colon cancer (10% and 3.3%, respectively). MP of 6892 CRCs identified significant differences between primary and metastatic sites and among BRAF/KRAS sub-types. Our findings are hypothesis generating and need to be examined in prospective studies. Specific therapies may be considered for different actionable targets in mCRC as revealed by MP.

Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study

Background:The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical.Methods:Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%).Results:A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003).Conclusions:Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation.

BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations

Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0.0000001). BRCA2 mutations in MSH2/MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors (P < 0.0000001). Approximately 15% of EGFR mutations found may be actionable through TKI therapy, including N700D, G719D, T725M, T790M, and E884K. NTRK gene mutations were identified in MSH2/MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency.

Patterns of care and outcomes of older versus younger patients with metastatic pancreatic cancer: A Fox Chase Cancer Center experience☆

BACKGROUND Older patients with metastatic pancreatic cancer (mPC) are poorly represented in clinical trials. We compared patterns of care and outcomes of patients with mPC < and >65 yrs (Group 1 and Group 2, respectively) treated at Fox Chase Cancer Center (FCCC) to identify predictors of survival and better understand the treatment approaches. METHODS Charts of 579 patients with mPC treated at FCCC from 2000 to 2010 were reviewed. Group 1 and Group 2 were compared with respect to baseline, treatment characteristics, and overall survival (OS) after diagnosis of metastatic disease. RESULTS 299 patients in Group 1 (median age 57) and 280 patients in Group 2 (median age 73) were evaluated. Patients in Group 2 were less likely to receive any chemotherapy for mPC compared to Group 1 (65% vs 75%, p=0.001) and if treated were less likely to receive more than one agent (37% vs 53%, p<0.001). Survival was comparable between the two groups (p=0.16) and Charlson Co-morbidity Index did not emerge as a prognostic factor. Longer OS was associated with higher number of agents used in both groups (p<0.001). Liver metastases conferred worse survival (p=0.02) while lung metastases conferred better survival in both groups (p=0.002). CONCLUSIONS Older mPC patients are less likely to receive chemotherapy and receive fewer agents yet have similar OS compared to younger patients. OS improves with increasing number of agents, supporting the use of combination chemotherapy in healthy older patients. Our findings encourage enrollment of older patients with mPC with good performance status onto clinical trials with stratification by site of metastases.

Cytotoxic Therapy in Advanced Pancreatic Cancer: Where We Are and Where We Are Headed

Pancreatic adenocarcinoma is the fourth leading cause of cancer-related deaths in the United States. Most patients are diagnosed at a late stage with poor outcomes despite recent advances in chemotherapeutic approaches. Gemcitabine therapy has been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer until recent studies showed improved outcomes with chemotherapy combinations, albeit with higher toxicity. We are now faced with the challenge of combining cytotoxic chemotherapies with targeted and novel agents. We hope that ultimately these drug combinations will be selected based on biomarkers, and such therapies will prolong patients’ lives and reduce toxicity further. The use of chemotherapy in the treatment of metastatic pancreatic adenocarcinoma in the current era and future directions is reviewed in this chapter.

Nutritional status and outcomes of older versus younger patients (pts) with metastatic pancreatic cancer (mPC).

386 Background: Older mPC pts are less likely to receive chemotherapy (Ctx) and receive fewer agents compared to younger pts, yet have similar overall survival (OS). Both obesity and malnutrition are linked with poorer outcomes in pancreatic cancer. We evaluated the effect of body mass index (BMI) and nutritional state on survival in 65 y (GpB) mPC pts. Methods: With IRB approval, we retrospectively analyzed charts of 579 mPC pts treated between 2000 and 2010. GpA and GpB were compared based on BMI alone ( 25) and also their nutritional status (poor: albumin 15% during disease course with any BMI; good: Alb>3.5 + Wt loss 20; intermediate: all others). Log-rank tests and Cox proportional hazards models were used to analyze OS and Fisher’s exact test to compare categorical variables. Results: There were 299 pts in GpA (median age 57yr) and 280 pts in GpB (median age 73 yr). Information on BMI/albumin was missing for 126 pts; total study populati...

Abstract LB-023: Plk2 loss occurs commonly in colorectal carcinomas but not in adenomas

Plk2 is a target of p53. Our previous studies demonstrated that in the wild-type p53 context, Plk2 impacts mTOR signaling in the same manner as TSC1, and human tumor cells deficient in Plk2 grew significantly larger than control tumor cells. Other investigators have demonstrated that Plk2 phosphorylates mutant p53 in a positive feedback loop. We investigated Plk29s tumor suppressor functions as they relate to mTOR signaling. Archived pathology specimens from 12 colorectal adenocarcinomas (4 early stage and 8 advanced stage) were stained for phosphorylated mTOR (serine 2448), phosphorylated ribosomal S6 (Serine 235/236), Plk2, p53, Ki67, and glucose transporter 1 (Glut1). We show that Plk2 is expressed in normal colon epithelium, with a punctate staining pattern in the supranuclear region. In colorectal adenocarcinoma, Plk2 demonstrates partial loss of expression, complete loss of expression, or disrupted expression manifested as irregular or abnormal localization. Loss of Plk2 expression is more pronounced in the invasive front in some cases. Strong expression of phosphorylated mTOR is observed in the invasive front, which is presumed to be less hypoxic. Phosphorylated S6 and Glut1 expression partially correlate with phosphorylated mTOR expression but appear more diffuse in some cases. p53 and Ki67 expression is diffuse, rather than specific to the tumor invasive front in the subset of cases examined. In order to determine at what stage in carcinogenesis Plk2 is lost, an additional 8 archived pathology specimens (tubular adenomas, sessile serrated polyps and hyperplastic polyps) from 6 patients were evaluated for Plk2 expression. All specimens were found to be positive for Plk2 expression. We conducted a TCGA search of Plk2 alterations in colorectal adenocarcinomas. Plk2 is mutated in only 8 of 498 (all p53 wild-type) cases. Neither Plk2 methylation (in the gene body not in the regulatory region CpG islands and shores) nor copy number changes correlated with mRNA expression changes and appeared to be independent of p53 status. Loss of Plk2 expression along with accentuated expression of phosphorylated mTOR, phosphorylated S6, and Glut1 at the invasive front at least in some colorectal carcinomas is consistent with previous findings that an interaction between Plk2 and TSC1 / mTOR signaling molecules plays a role in tumor suppression during hypoxic conditions. Plk2 protein expression was found to be lost at the same stage in colorectal carcinogenesis as p53 genetic loss. The p53 dependence of Plk2 loss and tumor suppressor function as they relate to mTOR signaling may have therapeutic implications. Citation Format: Elizabeth M. Matthew, Zhaohai Yang, Suraj Peri, Namrata Vijayvergia, Amriti Lulla, Eric Ross, Wafik S. El-Deiry. Plk2 loss occurs commonly in colorectal carcinomas but not in adenomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-023.

Abstract 1600: A multiplexed marker-based algorithm for diagnosis of carcinoma of unknown primary using circulating tumor cells

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Abstract: Real-time, single-cell multiplex immunophenotyping of circulating tumor cells (CTCs) is hypothesized to inform diagnosis of tissue of origin in patients with carcinoma of unknown primary (CUP). In 20 to 50% of CUP patients, the primary site remains unidentified, presenting a challenge for clinicians in diagnosis and treatment. Invasive tissue biopsy is the gold standard for diagnosis but improved methodology is needed. We developed a post-CellSearch CTC assay using multiplexed Q-dot or DyLight conjugated antibodies with the goal of detecting multiple markers in single cells within a CTC population. We adapted our approach to size-based CTC enrichment protocols for capturing CTCs and subsequent immunofluorescence (IF) using a minimal set of markers to predict the primary sites for common metastatic tumors. The carcinomas are diagnosed with cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor 1 (TTF-1), estrogen receptor (ER) or prostate-specific antigen (PSA) as the minimal set of informative markers. IF has been optimized in cultured tumor cells with individual antibodies, then with conjugated antibodies to form a multiplex antibody set. With IF, we evaluated antibodies specific to these 5 markers in lung, breast, colorectal, and prostate cancer cell lines and blood samples from metastatic prostate and breast cancer patients. Our technological advance provides a noninvasive, inexpensive, diagnostic blood test as an adjunct to routine tissue biopsy. Its further implementation requires prospective clinical testing. Citation Format: Elizabeth M. Matthew, Lanlan Zhou, Namrata Vijayvergia, David T. Dicker, Karen S. Gustafson, Harry S. Cooper, Eric A. Ross, Bora Lim, Ramdane Harouaka, Si-Yang Zheng, Nicholas E. Lamparella, Joseph J. Drabick, Cristina I. Truica, Zhaohai Yang, Wafik S. El-Deiry. A multiplexed marker-based algorithm for diagnosis of carcinoma of unknown primary using circulating tumor cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1600. doi:10.1158/1538-7445.AM2015-1600