EMBARGOED FOR RELEASE:
October 28, 2008, 6:00 PM (EDT)

CONTACT: Dan Sweet
571-483-1355
dan.sweet@asco.org
Onsite: 954-602-6819

-- KRAS Status Predicts Panitumumab Response in Colorectal Cancer Patients;
EGFR Mutations in Blood Could Identify Lung Cancer Patients Most Likely to Respond to Erlotinib; Tumor Protein May Identify Patients Who Could be Spared Difficult Pancreatic Cancer Surgery --

Hollywood, FL— New research on the rapidly advancing field of molecular cancer markers was released today in advance of the second Annual Meeting on Molecular Markers in Cancer, being held October 30-November 1 in Hollywood, FL. The meeting is co-sponsored by the American Society of Clinical Oncology, the National Cancer Institute and the European Organisation for Research and Treatment of Cancer.

Molecular markers are alterations in genes and proteins that are associated with different types of cancer, but also vary from individual to individual. This field is one of the most promising areas in cancer research; continued progress will enable physicians to select the most appropriate treatments and estimate prognosis based on the unique molecular makeup of each patient’s cancer.

“The findings of these studies support our increasing focus on personalized medicine, in which we’re treating a patient’s individual tumor according to its biology—not just its location and stage,” said Ramona Swaby, MD, attending physician at Fox Chase Cancer Center and moderator of the press briefing. “The ability to personalize patient care based on a cancer’s molecular makeup will continue to improve outcomes, help patients avoid therapies that may not be effective, and potentially reduce the cost of cancer care.”

Study findings include:

• Data showing that panitumumab (Vectibix) is only likely to be effective for treating advanced colorectal cancer in patients whose tumors contain the normal form (wild-type) of the KRAS gene, and not the mutated form of the gene; the finding builds on recent studies about the predictive value of KRAS mutations.

• Patients with metastatic non-small cell lung cancer whose blood and tumor tissue contain a mutated form of the EGFR gene experience faster tumor growth and do not live as long following erlotinib (Tarceva) treatment as patients who have an EGFR mutation only in their tumors. Since tumor tissue is difficult to obtain and test for EGFR mutations, the study also suggests that a blood test to detect EFGR status in patients with this disease could serve as a useful substitute for tumor testing.

• Patients with pancreatic cancer whose tumors do not have a protein called S100A2 live twice as long after pancreatic cancer surgery as patients whose tumors contain high levels of this protein; this finding could potentially spare some patients from this difficult surgery.

Information for Media: www.asco.org/MMMpresskit08 

Relevant Links on ASCO’s Cancer.Net:

• Cancer.Net Guide to Colorectal Cancer
• Cancer.Net Guide to Lung Cancer
• Cancer.Net Guide to Pancreatic Cancer
• Personalized Cancer Medicine: Translating Breakthroughs in Biology into Better Treatment for Patients

KRAS Status Predicts Response to Panitumumab in Patients with Progressive Metastatic Colorectal Cancer

Combined data from four clinical studies show that the drug panitumumab (Vectibix) is only likely to be effective for treating advanced colorectal cancer in patients whose tumors contain the normal form (wild-type) of the KRAS gene, and not the mutated form of the gene. Panitumumab is a targeted therapy that blocks the epidermal growth factor receptor (EGFR) on cancer cells.

Earlier this year, another group of researchers reported similar findings from a study evaluating KRAS status and response to different EGFR-targeted therapy called cetuximab (Erbitux). They evaluated patients with newly diagnosed metastatic colorectal cancer, and found that only those whose tumors had the normal form of the KRAS gene responded to treatment with cetuximab, but not patients whose tumors contained a KRAS mutation.

“The KRAS biomarker has redefined the risk-benefit profile of EGFR inhibitors by identifying patients with metastatic colorectal cancer who are most likely to respond to treatment,” said lead author Daniel Freeman, PhD, principal scientist, oncology research at Amgen, Inc., the manufacturer of panitumumab. “Being able to determine which patients will benefit from targeted therapies like panitumumab will reduce the burden of therapy for individual patients and the overall costs associated with cancer treatment.”

Panitumumab is approved in the United States as a single-drug treatment for metastatic colorectal cancer that expresses EGFR and persists despite prior chemotherapy that included irinotecan, oxaliplatin, and a fluoropyrimidine (such as 5-fluorouracil). It is approved in Europe and Canada for the same indication, with the additional requirement that the patients’ tumors contain the normal form of the KRAS gene.

The current study is based on the pooled findings from four previous studies that evaluated the effectiveness of panitumumab for metastatic colorectal cancer that persisted despite prior chemotherapy. The authors of the current study re-analyzed these data to examine the relationship between the effectiveness of the drug and KRAS status in 715 patients.

They found that none of the patients whose tumors had mutated KRAS responded to panitumumab (defined as tumor shrinkage or a halt in tumor growth), compared with 13.7 percent of those with normal KRAS genes. Progression-free survival was nearly twice as long (14.1 months versus 7.3 months) and overall survival was 37 percent longer (8.3 months versus 5.7 months) among patients with the normal form of the KRAS gene, compared with those who had mutated KRAS.

Efficacy of panitumumab monotherapy in relation to KRAS mutational status for treating metastatic colorectal cancer (mCRC) from four clinical studies
D. Freeman, R. Amado, M. Wolf, M. Reiner, E. Van Cutsem, M. Peeters, S. Siena, J. Hecht, J. Berlin, D. D. Chang
Background: Approved in the US for the treatment (tx) of chemorefractory mCRC, panitumumab is a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR). From a randomized phase 3 trial, wild-type (WT) KRAS is required for panitumumab monotherapy activity in mCRC patients (pts; Amado JCO 2008). In Europe and Canada, panitumumab has been approved for the treatment of chemorefractory mCRC pts with WT KRAS. The objective of this analysis is to associate KRAS mutational status with efficacy from pooled data from 4 clinical studies of panitumumab.
Methods: This analysis included data from 4 panitumumab monotherapy studies (Van Cutsem JCO 2007 & Annal Oncol 2007; Hecht GI Cancers Symp 2008; Berlin ASCO 2006). All studies required radiographic disease progression on prior fluoropyrimidine-, irinotecan-, and oxaliplatin-containing chemotherapy; all but 1 required EGFR staining by immunohistochemistry. KRAS genotype (WT or mutant [MT]) was identified using real-time PCR (DxS kit, Histogenix) from fixed primary or metastatic tumor samples. Tumor responses were assessed centrally in 3 studies.
Results: Across all studies, 795 pts received panitumumab and had tumor samples available for testing; of these pts 715 (90%) had tumor samples analyzable for KRAS. In pts with WT KRAS, the response rate was 13.7%. 320 (45%) pts had tumors with a KRAS mutation (table); no response was observed. Progression-free survival (PFS) and overall survival (OS) favored pts with WT KRAS receiving panitumumab; for PFS, the hazard ratio (HR) = 0.42; 95% CI: 0.36-0.50; for OS, the HR = 0.63, 95% CI: 0.53-0.74. Patients with WT KRAS had a longer median PFS and OS times than MT KRAS group.
Conclusions: Consistently across all 4 clinical studies, responses with panitumumab monotherapy were observed only in mCRC pts with WT KRAS. KRAS appears to be a valid predictive biomarker in selecting mCRC pts for panitumumab monotherapy.

KRAS Status	WT 395 (55)	MT 320 (45)
Objective Response Rate (95% CI) CR- n (%) PR- n (%) SD- n (%)	13.7% (10.4, 17.5) 1 (<1) 53 (13) 151 (38)	0% (0, 1.2) 0 (0) 0 (0) 46 (14)
Median PFS (95% CI), wks	14.1 (11.6, 15.4)	7.3 (7.1, 7.4)
Median OS (95% CI), mos	8.3 (7.5, 9.1)	5.7 (5.0, 6.4)

 

EGFR Mutations Detected in the Blood in Advanced Lung Cancer Patients
Predict Poorer Outcomes after Erlotinib Treatment

Investigators found that people with metastatic non-small cell lung cancer (NSCLC) whose blood and tumor tissue contain a mutated form of the EGFR gene experience faster tumor growth and do not live as long following erlotinib (Tarceva) treatment as patients who have an EGFR mutation only in their tumors. Erlotinib is a targeted therapy that blocks the epidermal growth factor receptor (EGFR) protein found in many cancer cells.

“These findings tell us two things. First, patients who have EGFR mutations in both their blood and tumor tissue have a worse outcome than those with tumor mutations only. This supports the hypothesis that when tumors become more aggressive, the degree of mutant DNA circulating in the blood rises,” explained Miquel Taron, PhD, head of the molecular biology laboratory at the Catalan Institute of Oncology in Barcelona, Spain, who presented the data. “And second, EGFR mutations identified through a blood sample could be a valid surrogate for tumor biopsy. This is important because in about a third of patients with metastatic non-small cell lung cancer, we are unable to biopsy adequate lung tissue to analyze for the EFGR mutation.”

Erlotinib is approved to treat locally advanced or metastatic non-small cell lung cancer that persists despite at least one prior regimen of chemotherapy. In this study, researchers compared response to therapy, progression-free survival and overall survival between 91 patients with stage IV NSCLC who had EGFR mutations only in their tumors and 120 patients with mutations in both their tumor tissue and serum (blood).

Response to therapy with erlotinib was similar between the two groups (67 percent). However, patients with mutations only in their tumors had longer progression-free survival than patients with EGFR mutations in both their tumor tissue and blood cells, (17 months versus 12 months). Patients in the former group also experienced improved median survival (27 months versus 20 months).

Additionally, when researchers further analyzed serum mutations, they found that patients with mutations in a part of the EGFR gene called exon 19 lived more than twice as long (32 months) as patients with an exon 21 mutation in the serum called L858R (14 months).

EGFR mutations (muts) in tissue and in serum DNA from stage IV non-small-cell lung cancer (NSCLC) patients (p) prospectively treated with erlotinib
R. Rosell, C. Queralt, J. Sanchez, T. Moran, A. Pradas, C. Mayo, M. Berdiel, J. Bertran, M. Molina, M. Taron
Background: We evaluated EGFR muts in tumor and matched serum at baseline and their role as a predictive marker in a multicenter trial of first- and second-line erlotinib in stage IV NSCLC p with EGFR muts in tumor.
Methods: 2281 NSCLC p were screened for EGFR muts in tumor; 327 p had muts. 211 stage IV p with muts were treated with erlotinib, and EGFR muts in paired serum were assessed in these p. EGFR mut testing in both tumor and serum was performed centrally. EGFR exon 19 deletions were studied by length analysis of fluorescently labeled PCR products and the exon 21 L858R mut by a PCR Taqman assay.
Results: EGFR mut status in the serum matched that in the tumor tissue in 120/211 p (57%), in 45.6% of p with PS 0, in 57.3% of p with PS 1, and in 75% of p with PS 2 (P = 0.01). There were no differences in the metastatic patterns either according to the presence of muts in serum or according to the type of mut. Response rate was similar in p with muts only in the tumor and in p with muts in both tumor and serum (67%). Progressive disease was observed in 15/120 p with muts in serum vs 3/91 p with muts only in tumor (83.3% vs 17.6% of all 18 p with progressive disease; P = 0.004). Overall time to progression (TTP) was 13 months (m); TTP was 17 m for p with EGFR muts only in tumor and 12 m for p with muts in tumor and serum (P = 0.05). TTP for p with EGFR exon 19 deletion in serum was 13 m vs 10 m for p with L858R mut in serum (P = 0.02). Median survival (MS) was 25 m overall; MS was 27 m for p with EGFR muts only in tumor and 20 m for p with muts in tumor and serum (P = 0.08). MS for p with EGFR exon 19 deletion in serum was 32 m vs 14 m for p with L858R in serum (P < 0.001). 20 p with PS 2 had EGFR muts in serum; TTP was 32 m for 11 with exon 19 deletion and 7 m for 9 with L858R (P = 0.02). Type of mut, gender, and brain and bone metastases were independent variables for TTP, while type of mut, PS and brain metastases were independent variables for survival.
Conclusions: EGFR muts in serum could be an ancillary non-invasive method for genotyping and could help to identify the small subgroup of p (10.4%) who will initially progress to erlotinib.

Absence of S100A2 Protein in Tumor Cells Predicts Improved Survival after
Pancreatic Cancer Surgery

Researchers have found for the first time that patients with pancreatic cancer whose tumors do not contain the S100A2 protein live twice as long after pancreatic cancer surgery as patients whose tumors contain high levels of this protein.

“While this research is still at a very early stage, we’ve found that testing for the S100A2 protein could help us identify which patients will be most likely to benefit from surgery, which can be complicated and risky,” said Andrew Biankin, BMedSc, MB, BS, FRACS, PhD, head of pancreatic cancer research at the Garvan Institute of Medical Research and specialist pancreatic surgeon at Bankstown Hospital in Sydney, Australia and the study’s lead author. “Furthermore, these findings may provide a basis for the development of new treatments for a cancer where almost nothing works, potentially offering hope to those living with this aggressive disease.”

Of the more than 37,000 people diagnosed with pancreatic cancer in the United States each year, some 20 percent are candidates for pancreatectomy—surgery to remove part or all of the pancreas. Some of these patients undergo the Whipple procedure, an extensive and very complicated operation in which the head of the pancreas is removed as well as parts of the small intestine, stomach and other nearby tissues. Despite surgery, however, few patients survive the disease, and many of them live with impaired quality of life for several months after surgery.

Dr. Biankin and his colleagues evaluated the relationship between overall survival and levels of 17 different tumor proteins in 360 patients who had surgery as part of their treatment for pancreatic cancer. Of the proteins examined, only tumor levels of S100A2 predicted a patient’s outcome following surgery: patients with high levels of S100A2 had a median survival of 8.8 months, compared with 19.4 months among patients whose tumors did not contain this protein. The survival benefit observed in patients whose tumors lacked S100A2 also persisted in patients with cancer cells in nearby lymph nodes and in patients whose surgically removed tumors contained cancer cells in their margins.

The investigators explained that although little is known about the function of S100A2, it may have a significant role in pancreatic cancer. Based on these data, they are focusing on further understanding its molecular mechanisms to determine whether it may have potential as a therapeutic target.

Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer
A. V. Biankin, J. G. Kench, E. K. Colvin, C. J. Scarlett, E. A. Musgrove, S. M. Henshall, R. L. Sutherland
Background: Current methods of preoperative staging and predicting outcome following pancreatectomy for pancreatic cancer are inadequate. We evaluated the utility of multiple biomarkers from distinct biological pathways as predictive markers of response to pancreatectomy and patient survival.
Methods: We assessed the relationship of candidate biomarkers known, or suspected, to be aberrantly expressed in pancreatic cancer, with disease specific survival and response to therapy in a cohort of 601 patients.
Results: Of the 17 candidate biomarkers examined, only elevated expression of S100A2 was an independent predictor of survival in both the training (n = 162), and validation sets (n = 439, HR 2.19, 95%CI: 1.48 - 3.25; p < 0.0001) when assessed in a multivariate model with clinical variables. Patients with high S100A2 expressing tumours had no survival benefit with pancreatectomy compared to those with locally advanced disease, whereas those without high S100A2 expression had a survival advantage of 10.6 months (19.4 Vs 8.8 months) and a HR of 3.23 (95%CI: 2.39 - 4.33; p < 0.0001). Of significance, patients with S100A2 negative tumours had a significant survival benefit from pancreatectomy even in the presence of involved surgical margins (median 15.7 months; p = 0.0007) or lymph node metastases (median 17.4 months; p = 0.0002).
Conclusions: S100A2 expression is the best predictor of response to pancreatectomy for pancreatic cancer reported to date, and high S100A2 expression may represent the development of a metastatic phenotype. Prospective measurement of S100A2 expression in diagnostic biopsies has potential clinical utility as a predictive marker of response to pancreatectomy and other therapies that target loco-regional disease.

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