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Gastrointestinal Cancers Symposium (ASCO GI)

Ramesh K. Ramanathan, MD, Medical Director of the Virginia G. Piper Cancer Center Clinical Trials Program at Scottsdale Healthcare, discusses the phase III MPACT study that examined gemcitabine plus nab-paclitaxel (Abraxane) in patients with metastatic adenocarcinoma of the pancreas.

Ramanathan notes that the MPACT trial is the largest trial to be conducted in patients with pancreatic cancer. He adds that the trial was a large international, multi-institution, trial that provided very promising results for the combination, which has been a long sought after goal in pancreatic cancer.

In the trial, 842 patients were enrolled and randomized to receive the combination of nab-paclitaxel at 125 mg/m

 or gemcitabine alone. The median overall survival was 8.5 months for the combination compared to 6.7 for gemcitabine alone (HR = 0.72; 

 = .000015). Moreover, the time to treatment failure was significantly prolonged with the combination from 3.5 months to 5.1 (HR = 0.70; 

Ramanathan notes that, as expected, there was more toxicity with the combination of nab-paclitaxel and gemcitabine than gemcitabine alone. The most common grade 3 adverse events were neutropenia, fatigue, and neuropathy. The rate of febrile neutropenia was 3% for the combination compared to 1% for the single agent.

View coverage from the 2013 GI Cancers Symposium

Ramesh K. Ramanathan, MD, from the Virginia G. Piper Cancer Center, discusses the phase III MPACT study that examined gemcitabine plus nab-paclitaxel in patients with metastatic adenocarcinoma of the pancreas.

Dr. Ramanathan Discusses the Phase III MPACT Trial

William M. Grady, MD, Clinical Research Division, Fred Hutchinson Cancer Research Center, GI Cancer Prevention Program, Seattle Cancer Care Alliance, discusses results from a study that examined the association of intrinsic subtypes of colorectal cancer (CRC) with prognosis, chemotherapy response, and other factors.

The group of investigators from this study sought to find molecular markers that could help determine treatment options, Grady explains. This area of research has grown in recent years with the continued focus on targeted therapies. The identification of molecular changes in colon cancer will help identify the most appropriate targeted therapy, resulting in optimal outcomes.

In the study, researchers examined gene expression data from 188 patients with CRC, followed by validation through the examination of 543 patients. Overall, 3 intrinsic subtypes of CRC were identified based on the biology of the tumors. Moreover, these subtypes were each associated with varying outcomes and treatment sensitivity (Find out more, 

Grady believes this trial will usher in a new era for molecular diagnostics in CRC. Furthermore, he states, it will soon be possible to examine molecular changes in CRC overtime and personalize treatment based on these changes.

William M. Grady, MD, from the Fred Hutchinson Cancer Research Center, discusses results from a study that examined the association of intrinsic subtypes of colorectal cancer with prognosis, chemotherapy response, and other factors.

Dr. Grady Discusses Molecular Subtypes in Colorectal Cancer

A simple blood draw could lead to life-prolonging adjustments in treatment for patients with pancreatic cancer, the authors of a study have found.

By profiling the gene expression of circulating tumor cells in blood, the investigators have demonstrated, it is possible to predict whether specific patients with pancreatic cancer will respond to standard chemotherapy combinations, are becoming resistant to such treatments, or are experiencing progression of their disease. The results of the ongoing prospective study, being conducted at Memorial Sloan-Kettering Cancer Center in New York, were presented at the 10th Annual Gastrointestinal Cancers Symposium held January 24-26 in San Francisco, California. The findings may help physicians choose the most effective therapies for individual patients and, when necessary, switch to different treatments. Picking effective treatments is crucial in pancreatic cancer because the disease is uniformly lethal, with survival <5% at 5 years and cytotoxic drugs the only current method for extending life, the authors wrote. The blood tests could also eliminate the need for repeated tumor biopsies, which can be difficult to obtain in patients with the disease, ASCO wrote in a statement released prior to the conference.

While there have been previous studies of pharmacogenomics modeling in other cancers, this is the first to examine the response to a cocktail of drugs, ASCO reported.

“We’re making some progress in developing more effective treatments; in the last 3 years, a drug cocktail, FOLFIRINOX, has brought dramatic improvement, and a combination of gemcitabine and nab-paclitaxel has been shown to improve survival, too,” said Kenneth Yu, MD, of Sloan-Kettering, an author of the study. “Now, the problem remains that we don’t have a validated biomarker to help us choose effective treatments for each individual patient we see. The purpose of this study was to see whether a pharmacogenomic analysis of circulating tumor cells could help.”

In the study, which has enrolled 50 of an anticipated 60 patients with unresectable pancreatic cancer, 10 mL of peripheral blood is collected prior to treatment with chemotherapy, and again at disease progression. Using a new model created by CellPath Therapeutics, in Baltimore, Maryland, investigators isolate tumor progenitor cells, extract total RNA, and perform gene-expression analysis to test how the variations in specific tumors affect response to 12 chemotherapy drug combinations.

Participating doctors are blinded to the results of the profiling, and are treating the patients as they normally would.

So far, investigators have analyzed expression differences between 30 patients with continued response to their treatments and 20 patients whose disease has progressed, Yu said. Analysis was performed at both the molecular pathway and individual gene levels.

While the results of the profiling were not used to guide treatment in the study, researchers found that 6 patients who received chemotherapies predicted to be effective had better outcomes than 8 patients who received treatments predicted to be ineffective (average time to disease progression 7.3 months vs 3.7 months, 

Among the 20 patients who experienced tumor progression, researchers found that chemotherapy sensitivity profiles had changed, suggesting the need for different treatment regimens. Specifically, disease progression and treatment resistance were accompanied by increased dysregulation in the Rb1 and PLC biological pathways and changes in the ErbB3, ARE/Nrf2, and insulin pathways, ASCO said in its statement. Among patients with stage IV cancers who experienced progression, major differences were seen in the E2F1 and NFκB pathways, ASCO stated.

“Hedgehog pathway overexpression was associated with resistance to gemcitabine, but clinical response to 5-FU-based treatment,” the authors noted.

The investigators concluded that this method of gene-expression profiling can be performed reliably in pancreatic cancer, and that it can predict treatment response and identify key pathways associated with treatment resistance.

CellPath is testing the model in other cancers, too, Yu said.

“Picking the right first regimen is really critical,” he said, “because if patients don’t respond, they may become too ill to get another line of chemotherapy.”

Yu added that the model could also help doctors identify patients unlikely to respond to any therapies.

“That would be important to know, as well,” he said, “so that doctors can work to improve the quality of life of those patients, instead of giving them drugs that are really toxic.”

	Sangar V, Ricigliano M, O’Reilly EM, et al. Use of pharmacogenomic modeling in pancreatic cancer for prediction of chemotherapy response and resistance. Presented at: 10th Annual Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Abstract 142.

Gene Profiling of Circulating Tumor Cells May Predict Treatment Response in Pancreatic Cancer

Using a new classification system that categorizes colorectal cancers (CRC) by tumor gene expression patterns, researchers have determined that tumor prognosis and response to adjuvant chemotherapy in CRC vary according to molecular subtype. The research was presented at a press conference prior to the 10th annual Gastrointestinal Cancers Symposium.

Researchers developed the molecular classification system based on gene expression data from 188 patients with CRC, and then validated the system in tumor samples from 543 patients with stage II and III disease. Subtypes were analyzed for correlation to clinical information, mutations in the kinome (protein kinases in the genome), known molecular marker status, and chemotherapy response.

The analysis found that CRC consists of at least three major intrinsic subtypes, A, B, and C, based on three biological hallmarks of the tumor: epithelial-to-mesenchymal transition (a biologic change associated with more aggressive tumors), deficiency in mismatch repair genes (a tumor characteristic that leads to high rates of genetic alterations), and the rate of cell proliferation. These features are known to independently affect outcomes in patients with cancer.

Of the samples analyzed, 21.5% belonged to subtype A, 62% to subtype B, and 16.5% to subtype C.

A 10-year follow-up found that patients with subtype C had the worst outcomes, showed no benefit from adjuvant chemotherapy, and had a mesenchymal gene expression phenotype. Patients with subtypes A and B had better outcomes, benefited from adjuvant chemotherapy, and had a more proliferative and epithelial phenotype.

In addition, compared with subtype B, subtypes A and C had higher rates of mutation frequency in many genes, including those that play an important role in CRC development and growth, such as 

The classification system could be used to determine disease prognosis and individualized treatment plans. For instance, in stage II disease, clinical and pathological factors do not always accurately identify patients who face a high risk of relapse after surgery and might therefore benefit from additional therapy. Furthermore, currently available genomic classifiers such as Oncotype and ColoPrint are not linked to clear recommendations for postoperative chemotherapy. Finally, in patients with later-stage disease who have undergone treatment, currently available tests cannot help individualize therapy—the researchers’ goal in developing the classification system.

“There’s no way to select treatment for individual patients. Currently, only 

 has been established as a predictor of anti-

 treatment activity,” said study co-author Josep Tabernero, MD, at the press conference. Tabernero is director of Clinical Research at Vall d’Hebron Institute of Oncology in Barcelona, Spain.

Dr. William Grady Discusses Molecular Subtypes in CRC

“This study clearly shows that there are different subtypes in colorectal cancer with completely different biological and clinical characteristics,” Tabernero said. “We hope that with continued research, we’ll be able to develop new molecular tests based on this classification system, not only to identify patients needing more aggressive adjuvant treatment, but also to help us to predict which patients will respond to specific chemotherapy drugs and targeted agents, regardless of cancer stage.”

Researchers are currently validating the classification system in stage IV CRC. “I predict that in the next 2 or 3 years we and other research teams will have several gene expression signatures developed, informed by ours and other studies,” Tabernero said.

	Simon I, Roepman P, Schlicker A, et al. Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT). Presented at the 10th annual Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Abstract 333.

Using a new classification system that categorizes colorectal cancers by tumor gene expression patterns, researchers have determined that tumor prognosis and response to adjuvant chemotherapy in CRC vary according to molecular subtype.


Colorectal Cancer Prognosis and Response to Chemotherapy Vary by Molecular Subtype

Patients with advanced esophagogastric adenocarcinoma who received the chemotherapy drug docetaxel as a second-line therapy after progressing after their first line of treatment experienced a longer period of overall survival as well as a better quality of life compared with patients who received active symptom control.

The results of the phase III study, presented at the 2013 Gastrointestinal Cancers Symposium, held January 24—26 in San Francisco, California, represent some of the first definitive evidence that this widely used method of second-line therapy for esophagogastric cancer does have measurable benefits in a disease characterized by poor prognoses and a low median survival.

“Because of the aggressive nature of the disease, all patients who present with advanced disease and up to 70% of patients who present with early stage disease will ultimately progress after their chemotherapy,” said Hugo Ford, MD, director of cancer services at Addenbrooke’s Hospital in Cambridge, UK, and lead author of the study. “For these patients, we know that the average survival time is only 3 or 4 months.” He added that although second-line chemotherapy is commonly prescribed, “there’s very little good evidence to show that treatment improves quality of life.”

In this trial, 168 patients with locally advanced or metastatic esophagogastric adenocarcinoma whose disease progressed within 6 months of initial chemotherapy were randomized to receive either docetaxel 75 mg/m2 every 3 weeks for up to 6 cycles (n = 84) or active symptom control, which could include any treatment that the physician deemed an appropriate choice to manage the disease (n = 84). The primary endpoint of the study was overall survival (OS), with secondary endpoints including response rate, toxicity, health-related quality of life (HRQL) and healthcare resource use.

The study found that patients who received docetaxel as second-line treatment experienced a median OS of 5.2 months (95% confidence interval [CI], 4.1-5.9), a significant improvement over the median OS of 3.6 months (95% CI, 3.3-4.4) in the active symptom control arm (HR = 0.67; 95% CI, 0.49-0.92; 

Additionally, Ford reported that there were no significant differences observed in global quality of life or function between the two groups, and those who received docetaxel had a significantly better symptom score for pain than those who received active symptom control. Ford also said that very fit patients with the longest interval between previous chemotherapy and relapse or progression fared better, as was expected. Benefits were observed across all patient groups, and no cohort appeared to do worse if they received chemotherapy, Ford said.

Dr. Hugo Ford on the Phase III COUGAR-02 Study

“We conclude as a result of this trial that docetaxel should be the standard second-line treatment for esophagogastric cancer, and we think it’s likely to be the standard arm against which future treatments should be compared,” Ford said.

According to the National Cancer Institute, approximately 39,000 new cases of cancer of the esophagus, stomach, and esophagogastric junction were diagnosed in the United States in 2012.

	Ford H, Marshall A, Wadsley J, et al. Cougar-02: a randomized phase III study of docetaxel versus active symptom control in advanced esophagogastric adenocarcinoma. Presented at: 10th Annual Gastrointestinal Cancer Symposium; January 24—26, 2013; San Francisco, California. Abstract LBA4.

Patients with advanced esophagogastric adenocarcinoma who received docetaxel as a second-line therapy experienced a longer period of overall survival as well as a better quality of life compared with patients who received active symptom control.

Second-Line Docetaxel Improves Survival and Quality of Life in Patients with Advanced Esophageal and Stomach Cancers

A retrospective analysis of the potential benefits of surgery following treatment with imatinib (Gleevec) suggests a clear benefit in both overall survival (OS) and progression-free survival (PFS) in patients with metastatic or recurrent gastrointestinal stromal tumors (GIST) when compared with those who received imatinib therapy alone. The findings were presented at the 10th Annual Gastrointestinal Cancers Symposium held January 24-26 in San Francisco, California.

GI stromal tumors are relatively uncommon, with approximately 4000-5000 new cases each year, according to the American Cancer Society. The tumors occur most frequently in the stomach (approximately 60%) and small intestine (approximately 30%), but may be found anywhere in the GI tract. Most patients are ≥50 years of age, and the disease is slightly more common in men.

Previous retrospective studies have shown survival benefits from surgery in GIST patients after treatment with imatinib, but these outcomes have not been compared with those of patients who did not have surgery, the focus of this study led by Seong Joon Park, MD, a fellow at Asan Medical Center in Seoul, South Korea. “Many clinicians think that adding surgery is beneficial to the patient if the patient is responsive to imatinib, but the clinical evidence for this is very scarce,” he noted.

Although patients respond to imatinib when used as first treatment for metastatic or recurrent GIST, most patients develop secondary resistance, said Park. For about one-third of these patients, residual lesions can be surgically removed, after considering tumor size and other patient characteristics.

For this study, researchers examined survival among 134 patients who showed clinical response to imatinib or achieved disease stabilization for at least 6 months. Those patients who had surgical resection of residual lesions after imatinib comprised the SI group (n = 42); their outcomes were compared with those who received imatinib therapy (IM) without surgery (n = 92). Patients in the SI group had surgical resection at a median of 19.1 months of treatment with imatinib.

After median follow-up of 58.9 months, PFS in the SI group was 87.7 months, versus 42.8 months in the IM group (

 = .001); OS was 88.8 months in the IM group but not reached in the surgery group (

 = .001). Factors associated with improved PFS, according to investigators, were low initial tumor burden, female gender, and presence of the 

Patient and tumor characteristics were similar between the SI and IM cohorts, with the exception of median age (51 and 58 years, respectively) and metastases to the peritoneum (12 in the SI group and 56 in the IM group). Park explained that these differences are a reflection of clinical practice, insofar as surgery is often recommended in younger patients with good performance status and can be difficult in patients with multiple peritoneal metastases.

“This study really provides provocative evidence that taking an aggressive approach surgically, in addition to medical treatment with imatinib, may, in fact, result in even longer survival of patients with GI stromal tumors,” said Neal Meropol, MD, Professor of Medicine and Division Chief, Department of Hematology and Oncology, at the Case Western Reserve University School of Medicine.

Park noted that it is very important for patients to find the right medical center for their treatment, with surgeons and multidisciplinary teams experienced in treating and managing GI stromal tumors. “Those two characteristics are key for patients in selecting an appropriate place to go for their treatment,” concluded Meropol.

	Park SJ, Ryu M-H, Ryoo B-Y, et al. The role of surgical resection following imatinib in patients with metastatic or recurrent GIST. Presented at: 10th Annual Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Abstract 62.

A retrospective analysis of the potential benefits of surgery following treatment with imatinib (Gleevec) suggests a clear benefit in both OS and PFS in patients with metastatic or recurrent GIST when compared with those who received imatinib therapy alone.

Gastrointestinal Cancers Symposium (ASCO GI) | Conference

Dr. Ramanathan Discusses the Phase III MPACT Trial

Dr. Grady Discusses Molecular Subtypes in Colorectal Cancer

Gene Profiling of Circulating Tumor Cells May Predict Treatment Response in Pancreatic Cancer

Colorectal Cancer Prognosis and Response to Chemotherapy Vary by Molecular Subtype

Second-Line Docetaxel Improves Survival and Quality of Life in Patients with Advanced Esophageal and Stomach Cancers

Surgery Following Imatinib Boosts Survival for GIST Patients