You may have heard the exciting data on PARP inhibitors for patients with mutations in the BRCA genes reported at ASCO 2009. Patients who carry these mutations are deficient in DNA repair which makes them very sensitive to PARP inhibitors which play a significant role in DNA repair.
Why does that matter for colon cancer? Well, the genetic predisposition HNPCC is caused by another DNA repair deficiency linked to mutations in MLH1, MSH2, MSH6, PMS1 and PMS2. The landmark sign for mismatch repair deficiency is microsatellite instability also called MSI.
This is the only good prognostic marker we have seen. Tumors with high MSI have usually better outcome, longer life,and lower risk of tumor recurrence.
There may be even more news for these patients. We are now running a clinical trial using PARP inhibitor developed by AstraZeneca for patients with metastatic colon cancer who have been treated with all standard of care therapies and whose tumors show MSI.
There are a number of centers who are participating in this trial including Swedish Hospital, Vanderbilt, University of Denver, NYU and USC as well as Palms Springs Cancer Center. The more we understand about the tumors the better we can develop treatment strategies such as the PARP inhibitors.
The very good news is that these drugs which are very targeted have usually very little side effects. If you are looking for clinical trials and have exhausted the standard therapies. Please contact me or any of the Centers mentioned above.
September 08, 2009 at 9:54 pm, Erica Paul said:
Hi Dr. Lenz,
I am 28 years old, and have been battling colon cancer with mets to the liver and lungs for about 2.5 years. I started on FOLFOX, was switched to FOLFIRI due to Oxaliplatin toxicity. Due to slight progression in tumor size, I was put back on FOLFOX but I go through an Oxaliplatin desensitizing process each time. I also received Avastin in the past and was switched to Erbitux back in January 09 and receive it currently on a weekly basis. I also have the HAI pump and my liver is treated with FUDR and Mitomycin. It is only a matter of time before the standard of treatments will no longer be an option for me, however, I hope that is not the case. I have been reading about the PARP inhibitors, and am very interested in finding out whether or not I am a candidate, and if it would be helpful in my treatment. Any information you can provide on this would be so appreciated. Also, based on the information I have given you about my diagnosis and treatment, do you feel that incorporating a daily asprin would be beneficial in my case?
Thank you so much for your time. Your blogs are wonderful, and you are indeed a blessing to those affected with this disease.
Sincerely,
Erica Paul
Reston, VA
September 09, 2009 at 9:49 am, Heinz-Josef Lenz said:
thanks for sharing this with us, i am sure you had avastin? but you did not mention it…..also because of your age were you tested for genetic predisposition? mismatch repair mutation? or microsatelitte instability? if it is not done you should do it, it has prognostic and predictive implication these pateints do better (and you are doing very well) and you may have additional treatment options such as the PARP inhibitors which are developed for tumors with this particular genetic make up. Where are you located? in addition to parp inhibitors there are a number of novel agents in clinical trials which show promise. cmet inhibitors, EPO906 and others we are developing our own drug targeting the colon cancer stem cells. Hope this helps.
September 09, 2009 at 9:37 pm, Erica Paul said:
Hi Dr. Lenz,
Thank you so much for providing such terrific information. I have been treated with Avastin, but unfortunately, my scans showed progression so my Oncologist discontunued use. I am treated in Fairfax, VA, and also at Sloan-Kettering Cancer Center by Dr. Nancy Kemeny. I will see her next week and will request the genetic testing you suggested. So far, I have only been tested for the K-RAS Mutation, and the result was negative. If you don’t mind, I would love to keep you posted on my progress. Thank you again- your information is very much appreciated.
Sincerely,
Erica Paul
September 10, 2009 at 9:38 am, Heinz-Josef Lenz said:
my pleasure and you are in good hands. please feel free to contact me anytime. HJL
September 10, 2009 at 3:06 pm, Michael Grinberg, M.D. said:
Dr. Lenz,
My wife has Stage 4 colon cancer (adenocarcinoma of the cecum, T3(V2)-N2-M1) diagnosed May 2008. After colectomy, she completed a course of FOLFOX6 w Avastin and had good markers. Three months later, she had skyrocketing CA-19-9, had 3 FOLFIRI treatments with lots of side effects, and is now on Erbitux & Avastin, with a course of palliative tomoradiation therapy to large abd tumors. Though she does not quite meet the criteria for Lynch syndrome, she DOES have + family hx. How can she get genetic testing for MSH2/microsatellite instability? Would she be a candidate for PARP inhibitors and/or methotrexate?
September 12, 2009 at 5:03 pm, Zaklina said:
Dr. Lenz,
My mother, age 50, has stage 4 colon cancer. She is on second line therapy of FOLFIRI w avastin. She has liver and lung mets. She has been enduring chemo every two weeks for the past year. The exception was a month off for colon then two months off for liver resection. She is praying for a chemo break. Is there a role for immunotherapy? Issels Immunotherapy was recommended. What is your opinion of this as an additional treatment, not to replace conventional chemo? She is Krass positive. We met you in July at your office and you are such an inspiration. My mother, Lena, left feeling like her options were plenty versus scarce. I am so grateful to you.
September 20, 2009 at 11:36 pm, Erica Paul said:
Hi Dr. Lenz,
This is Erica Paul. I left a couple of comments above, and you were kind enough to respond. My latest scan indicated growth in the three small tumors on my liver and also in the numerous pulmonary nodules. I had been receiving FOLFOX + Erbitux which has basically failed. I am now scheduled to have the SIRSpheres microspheres procedure with radiation to treat the liver tumors. My Oncologist suggests that we concentrate on the liver right now and deal with the lung mets later since they aren’t as big as a threat. What are your thoughts on the SIRSpheres microspheres procedure, and for do you think that it is a good treatment decision for someone with my case?
Thank you,
Erica
October 20, 2009 at 6:22 pm, Tom said:
I am an otherwise healthy 47yo with stage IV poorly differeniated adenocarcinoma of the colon. Interestingly, I have only lymph node involvement (abdominal, mediastinal, cervical), no solid organ involvement. I have a high MSI on path and have tested MSH6 positive. Treated since May, first with FOLFOX/Avastin for 9 treatments, then FOLFIRI/Avastin for additional 4 treatments – changed due to neuropathy. CEA came down from36 to 12 on folfox then stagnated there before switch to folfiri, no down to 7. CT’s have shown no progression, but no real regression of adenopathy.
I am interested in your PARP inhibitor protocols – would I be considered a candidate based on above? I live in Maine, followed at Dana Farber, but could travel as I have family in LA. Any thoughts?
Tom