Some of the most interesting data presented at ASCO was the data on MSI and 18qLOH in a European clinical trial.
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.
June 16, 2009 at 2:59 pm, Sue said:
I am on my last trtment with folfox 4 without Avastin thru the E5202 trial.
My markers were: Mss with 18q LOH deletion. I would like to know what percentage of survival at 5 yrs. that puts me at. Noone will tell me.
I know this is just statistical, but still would like to know.
June 16, 2009 at 7:53 pm, Heinz-Josef Lenz said:
that is great news that you received FOLFOX since wiht MSS you have an increased risk for recurrence and have benefit from 5-FU. there is no question about the 18q deletion. According to the publication of Watanabe with MSS and 18q you have a similar risk like stage III cancer which is always treated wiht FOLFOX. HJL
July 10, 2009 at 11:11 am, Sue said:
Hello again Dr. Lenz,
I finished my trtment with Folfox IV 3 wks ago. I am to get a CT scan and asked for a PET scan also. My Dr. ordered just a PET scan. Shouldn’t I receive both?? I had Stage II MSS/18q LOH deletion, surg. removed mod. diff, adeno, T3, N0, MX
Sue
July 10, 2009 at 5:19 pm, Heinz-Josef Lenz said:
usually would do a CT or combined CT/PET not PEt alone since small lesions are not picked up by pet they need to be larger than 5mm but these can be seen on CT. HJL
May 05, 2010 at 2:35 am, anon said:
I am a doctor and my father ,66 years old, had rectal tm and had an operation last week. Tm was 10 cm away from tha anal verge, CEA level was normal. Tm size was 2x5x3 cm (0.8 cm depth), subserosal invelvement was detected . Lymph Node was negative. Thus, tumor stage is 2a,T3N0M0. and MSI findings were present in the specimen. 18 q deletion is not known at the moment. What kind of treatment and further evaluations would you recommend for my dad? Chemo?Chemo+radiatherapy?
June 15, 2010 at 11:20 pm, Jodi said:
Hiello Dr. lenz. i’ve never posted here and hop I’m doing this correctly.
My mom has stage II Colon cancer no lymphnodes, T3NOMO, MSS and 18Q markers with poorly differentiated cells, High grade tumor.
Does Xelox, Folfox work best for this high risk type? Or is there another recomended chemo more effective for this. I know there is a study with Avastin. Is the 18Q marker high enough risk to use Avastin? Confused and running out of time to make the choice for type of chemo. I thought I’d ask for your input or explinations of chemo for this 18q MSS group? Thank you so much in advance for any input or help you can offer!
Jodi
September 23, 2010 at 11:21 am, Frances said:
Dear Dr. Lenz,
My mom has stage II colon cancer, MSI-H, no lymphnodes (negative out of the 27 scraped), and T3NOMO, and lymphocytes infiltrating(?). Not sure about the 18q deletions and what that is. She had surger about 3 weeks ago, and now we are getting conflicting opinion as to whether she should receive chemotherapy and targeted therapy. I’ve been reading lots of publications and articles online, but nothing is at all conclusive given the small data sample. Do you have any opinion or suggestions? Thanks.
September 23, 2010 at 12:06 pm, Kate Murphy said:
You might want to watch a webinar we just did with Dr. John Marshall that reviews choices in stage II colon cancer chemotherapy: Stage II Colon Cancer: Chemo or Not? Find Your Solution.
In it Dr. Marshall reviews MSI, and we look at the statistics for poorer outcomes when 5-FU chemo is used in MSI high stage II patients.
The webinar also looks at the lower risk of stage IIA (T3,N0,M0) tumors like your mom’s.
Expert recommendations are not to use chemotherapy in stage II colon cancer unless it has high-risk features.
Three clinical trials have shown that targeted agents Erbitux and Avastin don’t make chemo more effective in high-risk stage II or stage III colon cancer. Their use is not recommended.
Patients with stage II T3 colon cancer and MSI have a very good chance of survival in the 90 to 95 percent range at five years.
We hope this helps in your decision-making.
September 23, 2010 at 12:23 pm, Frances said:
Dear Kate,
Thank you so very much for this information…. I did watch the webinar you cited…..so even regular chemotherapy (non-targeted – non Avastin/Erbitux, i.e. 5-FU) is not recommended for patients with her cancer type? Our concern is that her tumor was pretty big (6.5cm) and it was obviously obstructing…..so even though it is T3, still we feel that perhaps she should receive the 5-FU? Nothing seems to be certain one way or another and we are living overseas so we do not even know if we have the latest information/technology/medicine.
September 23, 2010 at 1:01 pm, Kate Murphy said:
Dear Frances,
An obstruction is one of the high risk features that may call for chemotherapy.
So your mom’s case is a little more complicated.
However, one more test (which already might have been done when they determined that the tumor was MSI-H) can give you some important information.
Some MSI cancers are caused by an inherited mutation. These can be very large and obstruct the colon because they grow quickly. The pathologist can look for missing protein expression of MLH1,MSH2,or MSH6.
These are a clue to an inherited cancer called Lynch syndrome. Although there is usually a family history of uterine or colon cancers in Lynch families, there does not need to be.
If your mother’s tumor lacks expression of one of these genes, she should get some genetic testing to see if her tumor is an inherited one.
If so, she’ll need closer follow-up and you and any other children should be tested for that gene too.
Check the pathology report to see if there was immunohistochemical testing for MLH1,MSH2,or MSH6. If not, arrange for it. It’s important.
While this is scary, Lynch syndrome cancers have excellent prognosis. I’ve lived 28 years since my own first Lynch colon cancer (which did obstruct!)
September 23, 2010 at 1:32 pm, Frances said:
Dear Kate,
That is good to know really…and thank you for sharing your own experience. Thank you…..although nothing is certain and everyone is different, just to know that you lived for 28 years after made me feel so much better….my grandma (on my mom’s side) had colon cancer and died of colon cancer b/c it was terminal stage. I would imagine it is hereditary and probably likely Lynch. But I cannot seem to find in the pathology report anything about the missing protein expression of MLH1, MSH2 or MSH6. Is it a very problematic or invasive test to do? Will it be doable given that she is still recovering from surgery slowly?
Thanks.
September 27, 2010 at 10:42 am, Frances said:
Dear Kate,
There appears to be nowhere to perform the immunohistochemical testing you mentioned last week in my country. In the absence of that information, given her MSI – H and no lymphnodes but slighly obstructing tumor (about 4.5cm), based on Dr. Marshall’s webinar, it still appears that chemotherapy may not be recommended. My mom has some genes that are in fact supposed “antibodies” of her colon tumor. However, given that she has one of the high risk factors, we may still proceed with generic chemotherapy (adjuvant) (without the targeted therapy). Is there any possibility that the chemotherapy could potentially kill those antibodies and make her even more vulnerable to recurrence?
September 27, 2010 at 4:06 pm, Kate Murphy said:
Frances,
It is really hard to know what is meant by genes that are “antibodies”. Genes are usually not talked about in that way.
So I am puzzled.
So I can’t really answer your question. It is one that her doctor should explain further to you.
September 28, 2010 at 9:29 am, Frances said:
Dear Kate,
Sorry for my confusing question. The testing done here does not determine the amount of MSI it only says “histologic features suggestive of microsatellite instability” and that she has mild to moderate intratumoral lymphocytic response (0-2 per high-power field). But her tumor was 4 cm, not 4.5, but perforating and partially obstructing. They are doing one more test for her but it seems that her stage is so conflicting from everyone we hear from. I know you cannot make the decision for us – but if you would recommend one thing, do you think we should have her perform the immunohistochemical testing somewhere that renders it? Thanks again for all your advice/comments.
September 28, 2010 at 9:56 am, Kate Murphy said:
Frances,
One more clue! Intratumoral lymphocytic response is a good thing.
It means that the immune system reacted to the tumor and moved into the tumor itself, ideally to destroy cells.
Immune system response is not common in cancer. While the immune system recognizes bacteria or viruses as “bad outsiders” and mounts a response to destroy them, it is puzzled by cancer. Cancer isn’t exactly an outsider, so it takes something extra to get an immune response.
MSI cancers and, particularly those related to inherited Lynch syndrome, more often exhibit immune response by having lymphocytes (white blood cells) inside the tumor.
I strongly suggest that you find someone who can do some genetic testing of the tumor for loss of MLH2, MSH2, or MSH6 expression. Or you could have your mother’s blood tested for inherited mutations in these genes.
Was there actual perforation of the colon — a hole that allowed feces and possibly cancer cells to spill into the abdomen? That would make a difference and make the tumor high risk.
Otherwise, the MSI and lymphocytic invasion move it toward low-risk, with the possible risk that 5-FU might lower survival.
A tough call.
In what country are you?
Good luck.
September 29, 2010 at 2:29 am, Frances said:
Dear Kate,
Thanks for your message again. I really appreciate all your time and input. I am living in Taiwan now and unfortunately (although we will keep checking) we cannot seem to find a hospital that would perform the immunohistochemical testing. I am not sure what other test they are doing to my mom now it could be another genetic testing, so maybe that will provide some other clue. I will also keep checking to see if anywhere can do a test for loss of MLH2, MSH2 and MSH6 for her or blood test for mutations of these genes.
If that is affirmative – which would mean she has Lynch colon cancer, what would your recommendation be? I believe her report says the perforation is low /partial(?) (which is still a yes I think) and which would still put her in the high risk group right? Gosh, there is just no sure win-win situation here. If she is MSI and has lymphocytic response (and/or also Lynch) yet her tumor is perforating and partially obstructing, which would make her tumor high risk, I would imagine most people may still proceed with chemotherapy?
Thanks.
September 29, 2010 at 7:17 am, Kate Murphy said:
It sounds like time to take a deep breath and wait for the additional results.
This is a complex combination of high and low risks. There probably isn’t one simple solution.
Do the doctors have a recommendation?
They seem to be looking further right now.
Let’s wait for the tests and then mask decisions when all the evidence is in.
I know it is hard.
September 29, 2010 at 9:16 am, Frances said:
Dear Kate,
Thanks and you are right. It is time to wait and see. We actually found one or two hospitals here which can perform MSI determination test. Also, I mistook the perforation indication to be tumor not colon – my mom’s perforation seems to be in the tumor itself (macroscopic tumor perforation) and not in the colon? Does that make a difference? In any case this is not going to be an easy decision. My mom now seems to recall that my grandma (her mother) had adverse result from her chemotherapy about 11/12 years ago; she was almost 80 when it was diagnosed and it was terminal stage colon cancer. And if she had not had the treatment her prognosis was not too bad given the stage. But then she received chemotherapy which was not good right after the first session. That may be another fact we need to take into consideration.
But yes, it is a tough one.
October 02, 2010 at 8:39 am, Frances said:
Dear Kate,
We just found out that P53 and Ki-67 are two gene expressions that my mom has. So it appears that notwithstanding her MSI suggestive and lymphocytic response as well as no lymph nodes, she will probably need to proceed with chemotheraphy (due to P53 and perforation). Dr. Lenz had mentioned that the standard of care is FOLFOX? – Is that the same as 5-FU?
Thanks.