These data have been discussed by Kate Murphy. However I wanted to follow up with the significance of the data. To increase the risk of recurrence from 12% to 22% is not in any way or form helpful in the clinic, particularly because this outcome is independent of treatment effect.

In other words the technology used by Genomic Health did not result in any clinically meaningful markers which are helpful to decide whether chemotherapy should be given or not.

I was surprised that the data was presented like these are positive data because they have no impact on daily practices. These data need to be improved to make a difference so that they can be used to identify the patients who are at significantly higher risk.

Patients with stage II colon cancer have on average a 15 percent chance of cancer recurring. This is a big challenge! Should we treat everyone and treat many patients with no benefit to make sure we treat everyone who really is at higher risk.?

If we had a genetic marker set which could isolate these patients who are at higher risk, we could spare the ones with very low risk  from chemotherapy for 6 months.

The Genomic Health approach was not successful partly because they did not take advantage of the whole genetic make up. The technology is able to measure 40-50 thousand genes in one test and to figure out what signature would predict recurrence would be the solution.

In breast cancer they have developed a signature to predict recurrence risk and whether chemotherapy should be given.

• Preserved tissue from the QUASAR study was able to validate  a multiple panel of 7 genes that show the risk of recurrence for stage II colon cancer.  However, it could not prove that another 6 genes could predict who would benefit from treatment with 5-FU and leucovorin over surgery alone.   C3 has previously covered this analysis in depth. Dr. David Kerr in discussing the results emphasized the importance of combining recurrence risk scores with information about tumor stage and MSI status in making decisions about chemotherapy for stage II patients.
• A review of the PETACC-3 randomized clinical trial that compared infusional 5-FU to infusional 5-FU plus irinotecan found that MSI (microsatellite instability) status predicted both relapse free survival at three and five years and overall survival for stage II and III colon cancer.  However, the benefit was much stronger in stage II than in stage III leading Dr. Sabine Tejpar and her team to conclude that there may be biological effects of MSI that happen specifically in stage II.  As a hypothesis, she considered whether MSI prevents or reduces the ability of cancer to move into nearby lymph nodes. In contrast to a previous study that looked at adding irinotecan to bolus 5-FU, the PETACC-3 study found no benefit from irinotecan in stage III colon cancer.
• Prognostic molecular markers were quite different between stage II and stage III colon cancer in an analysis of several different markers in tumor tissue from the PETACC-3 study. While MSI or microsatellite instability was a strong marker of good prognosis in stage II, it lost its value as a prognostic marker completely in stage III.  p53 and the SMAD4 genes had prognostic value for stage III but not for stage II.  A marker previously identified with poor prognosis in stage II disease — loss of heterozygosity at 18q or 18qLOH — lost its prognostic value completely when analysed together with MSI in stage II and had no value in stage III.  In his conclusion Dr. Arnaud Roth questioned whether stage II and III colon cancers are biological different diseases rather than steps in continuous cancer development.

In discussionof the three molecular marker oral presentations at ASCO, Dr. Charles Fuchs pointed out the difference between

• Predictive markers that tell whether a particular treatment will be beneficial for an individual patient or not.
• Prognostic markers that tell how likely cancer is to recur or patients to survive regardless of treatment.

He questioned whether or not the gene analysis from the QUASAR trial is ready to help make clinical decisions about whether or not to treat stage II patients with chemotherapy and called for additional study of benefit from chemo in each of the recurrence risk groups.

Last year at ASCO, Dr. Daniel Sargent presented new data that patients with stage II disease with microsatellite instability do not only not benefit from 5-FU, but they may be harmed, and it was recommended to test for MSI in all stage II colon cancer patients and in the presence of MSI-high not to give 5-FU. For stage III colon cancer that was not the case.

This year, the PETACC-3 clinical trial was analyzed for MSI and did not show the same the same findings. It seems that chemotherapy does not harm these patients, and they may benefit.

This has been an ongoing controversy over the last couple of years with some studies showing benefit and other not. Last year’s ASCO showed there even may be harm.  What MSI means is now again up in the air. We can certainly state that the presence of MSI is a GOOD prognostic marker, meaning that these patients have a lower risk of tumor recurrence. However, if chemotherapy is beneficial or not is still not clearly answered.

Another finding in this clinical trial showed that 18q deletions are not prognostic in stage II disease when MSI status is known. That is important because our clinical trial E-5202 in the US assumed that patients with an 18q deletion are at higher risk for tumor recurrence independent of MSI, which may alter the interpretation of the clinical trial.

All these data show that we are learning a tremendous amount about the molecular make up of tumors, but it also shows that it is not easy to develop clinically meaningful markers. However, there is no doubt that new markers will be identified and validated over the years to come and will make our personalized oncology care a reality.

The data suggested that there was no benefit with the addition of Avastin, which was given not only for 6 months along with chemotherapy but 6 months in addition to FOLFOX for a total of 12 months.

Despite showing this was a negative clinical trial, when the investigators and Genentech looked at the 1 year disease free survival it appeared there was a potential transient benefit which lasted longer than the 1 year Avastin was given. Whether this is real or a fluke no one knows. However even considering that this is a real benefit, it would be very small may be 5 percent in 3 years. That means a 5% decrease of recurrence with one year of Avastin, but also means that many patients will be treated with no benefit.

Recent data have suggested that when Avastin was given  6 months longer some concerning side effects have been see in up to 10% of patients such as body pain interfering with daily function, dizziness, and central nervous system symptoms raising questions of the safety of Avastin given for a long time, particularly compared to little benefit at all (that benefit would be possible only under the best conditions). It became clear that studies using even longer administration of Avastin would be not indicated.

Fortunately there is a similar trial which was completed in Europe. The data will be hopefully available next year at ASCO and will answer whether this “transient” change is real which is more exciting for the tumor biology than clinical benefit or all a fluke.

Another question, of course, is will the clinical trials using Erbitux become effective in the adjuvant setting. In the US  N0147 is again open and only enrolling wild-type KRAS for this trial.

Surgeons at Memorial Sloan Kettering Cancer Center in New York followed 233 patients who began chemotherapy without surgery to remove their primary colon or rectal tumor. Almost 90 percent never had a problem with their tumor that needed intervention with surgery, radiation, or a stent. Only 7 percent required emergency surgery.

Researchers found among the group of 233:

• 16 patients (7 percent) needed emergency surgery because of an obstruction or bowel perforation.
• 10 patients (4 percent) had radiotherapy or a stent placed to relieve problems.
• 47 had the primary tumor removed at the same time they had surgery to remove metastastes.
• 8 had their colorectal tumor removed with surgery to place a pump in the abdomen to deliver chemo through the hepatic artery.

Use of Avastin, having a rectal tumor, or the number and size of metastatic tumors did not increase the risk of a complication in the primary tumor needing intervention.

Dr. George A. Poultsides and colleagues at Memorial Sloan Kettering concluded,

Most patients with synchronous, stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their intact primary tumor. These data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

The study was also presented as a poster at ASCO 2009.

SOURCE: Poultsides et al., Journal of Clinical Oncology, Early Release, June 1, 2009.

Last year we made a significant step forward in personalized oncology with the identification of a mutation in KRAS which is found  in about 40 percent of colon cancers.  This genetic switch predicts efficacy of drugs such as Erbitux and Vectibix. Since then the European Regulatory Agency EMEA approved KRAS testing in first-line metastatic colorectal cancer treatment, and since last Monday my colleagues in Europe including England  can use Erbitux in wild-type KRAS tumors for first-line treatment t which we in the USA can not do.

The data have been submitted to FDA for review to be able to use Erbitux or Vectibix in first line treatment, and we expect a decision in the next couple of months.

More and more American physicians test for KRAS mutations, but still mainly when we consider starting Erbitux or Vectibix. Increasingly in the US we are beginning to test with the diagnosis of metastatic colon cancer because the planning of treatment strategies may significantly change.

This year’s meeting asked the question: Do we have new information on additional markers?

There was promising data on PI3K mutations and BRAF mutations as well as on PTEN loss and expression of the EGFR ligands. It seems that PI3K and BRAF mutations may be not so clear as the KRAS mutation story. Studies presented at ASCO showed that the data are not consistent indicating that testing for these markers should not be done routinely yet.

PTEN loss is complicated and not easily clinically feasible since you need tissue from the metastatic site and no one likes to biopsy liver or lung lesions for a molecular test. The concordance of PTEN loss is not great when compared between primary and metastic site. This is because the method of PTEN inactivation is not a mutation but methylation which is dependent on the tumor’s environment which obviously is different in the primary tumor and liver or lungs mets.

The most promising is the EGFR ligand expression. Additional data suggested that high levels increase the probability of response to EGFR inhibitors. The problem is methodology and how to determine the cut off level. In other words, what is high and what is low.

Will there be a blockbuster new drug this year for colorectal cancer?  A big biomarker like KRAS was last year?  New directions in surgery? Radiation?

What’ll be in those “Late-breaking Abstracts” that no one sees until the meeting actually begins?

But even more than the abstracts, presentations, speeches, and posters that highlight research in cancer and patient care, is the chance to meet old friends and make new ones.  Nancy Roach, the C3 Board Chair, reminded me this morning of the New Orleans meeting that she and I did on a shoestring and the little French Quarter guesthouse with water that was only hot sporadically and the ceiling that fell on Nancy’s bed.

I’ve got a very nice, if not elegant, suite this year with a microwave if I had time to microwave anything, two TV’s, and a wide and comfy bed.   Best of all is the WiFi connection that keeps me in touch with my email, my blog, and my new forays into Twittering.

Yesterday was all about plunging in.  Picked up my nametag, without which I can’t get anywhere at all.  Found the Advocate Lounge, which will save my feet and life many times before Tuesday.  Got a nifty bag to carry my stuff … and there is lots of stuff to carry.

Two sessions on Friday focused on:

• Advanced concepts in clinical trial design with four excellent speakers who looked at ways to develop clinical trials that were faster, more innovative, and focused on patient variations.
• Controversial issues in rectal cancer management looked at whether tumors in the upper part of the rectum always need radiotherapy, when — if ever — is local excision right for early rectal cancer, and if adjuvant chemotherapy is necessary for stage II and III rectal cancer.

Got back on the bus at 6:00, which is the end of the ASCO day, and headed to a dinner with the FOCUS patient advocates training program.  FOCUS is run by the Research Advocacy Network and provides training before ASCO and support during the meeting for patient advocates.  It also funds registration and meeting costs so advocates can be here at ASCO.

Lots of old friends and some new ones at dinner including another woman who is just beginning her struggles with Lynch syndrome (hereditary nonpolyposis colon cancer) which has been part of my own life for the past twenty-five years . ..  much longer if I think back to my mother’s first colon cancer diagnosis when I was thirteen.

Patients who got ginger (Zingiber Officinale) in capsules twice a day for three days before chemo and three days after reported significantly less nausea that those who were treated with placebo.  All patients in the study also received standard anti-nausea therapy on the day of chemo.

Almost 650 patients, mostly women, were randomly assigned to ginger supplements or a placebo in a blinded trial that will be reported at the 2009 ASCO annual meeting.

Julie Ryan, PhD, MPH, who headed the study at the University of Rochester, told reporters at an ASCO press briefing,

As many as 70 percent of patients who undergo chemotherapy experience nausea and vomiting. We found that patients who received traditional anti-nausea drugs along with ginger supplements prior to chemotherapy experienced significantly less nausea associated with their chemotherapy. However, as with all supplements, patients should speak with their doctors first before taking ginger.

SOURCE: Ryan et al., Ginger for Chemotherapy-related Nausea in Cancer Patients, ASCO 2009 Abstract #9511.