Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards

ASCO University
May 13, 2015 8:54 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Emily Chan (Vanderbilt-Ingram Cancer Center) and Jan Nowak (NorthShore University HealthSystem). 

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ASCO University
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 13, 2015 9:03 AM


Patient Case

Age/Sex: 58/M

Medical History: The patient is a 58 year old man with a history of sarcoidosis, who has had chronic diarrhea with intermittent rectal bleeding for 3-4 years that he has attributed to medications for sarcoid.

He presented for a screening colonoscopy, which showed an ulcerated tumor causing mild obstruction in the sigmoid colon.  A separate small sessile polyp was found in the sigmoid.  The colonoscopy was otherwise normal to the cecum. Because of the neoplastic appearance of the sigmoid lesion, the decision was made to perform endoscopic ultrasound during the procedure.  By EUS, the tumor was circumferential, with invasion through the muscularis propria, extending distally to the level of the prostate and seminal vesicles.   More than 6 hypoechoic rounded lymph nodes suspicious for metastatic involvement were identified in the region of the iliac artery.   
CT of the abdomen and pelvis performed the next day revealed an indeterminant lesion in the left lung base and no metastatic lesions visualized in the abdomen or pelvis.  Three weeks later, the patient underwent low anterior resection with diverting colostomy after presenting with an acute abdomen.

Ten months after the original surgery, reversal of the colostomy was attempted, but diffuse peritoneal metastases were discovered during the surgery.  

Type of Tumor: colonic adenocarcinoma

Relevant Markers:  CEA= 7.1 ng/ml (reference 0.0 -3.0)

Prior Treatment History/Response: No neoadjuvant therapy

Co-morbidities: sarcoidosis, diagnosed five years previously


  • CT scan of the pelvis and abdomen:  Indeterminate 7.5 mm soft tissue nodule in the mid aspect of the left lung base. CT thorax recommended. Three-month follow up may be indicated. No evidence of metastatic lesions in the visualized upper abdomen.  3 mm nonobstructive calculus in the lateral aspect of the left kidney.
  • Pathology of the sigmoid resection specimen showed a mucinous adenocarcinoma with gross tumor peroration and pericolic abscess.  27 lymph nodes were retrieved and were negative for metastasis (Stage IIB).
Howard S. Hochster, MD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 19, 2015 4:53 PM

Thanks for the interesting case presenatation.

With a clinically perforated lesion, I would favor FOLFOX adjuvant therapy.  I am not sure that I would be disuaded from recommending this even for a patient with dMMR.  Who knows, soon we might only be using 3 months of therapy (C80702 almost accrued!).

Now that he has peritoneal carcinomatosis, he is at very high risk for rapid progression.  I would wonder if his tumor harbors a BRAF mutation, given the highly aggressive nature of his tumor, with a 10 month interval to recurrence and diffuse peritoneal involvement.  I would favor FOLFOXIRI, possibly with bevacizumab after a couple of cycles to allow surgical wound healing.


Howard S. Hochster, MD

Yale Cancer Center


ASCO University
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 13, 2015 9:09 AM


Discussion Questions

  1. Was there a role for adjuvant therapy after his original surgery?  If yes, what adjuvant chemotherapy would you recommend and why?
  2. What treatment would you recommend now?
  3. What additional information or testing would you want?


Chanjuan Shi
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 13, 2015 10:19 AM

Since the patient had stage IV colon ca, I would like to have the sample tested for RAS (or plus BRAF) mutations. Based on the NCCN guideline, the sample should also be tested for microsatellite instability. According to the pathology report, it is a mucinous carcinoma, which is frequently seen in MSI-high colorectal cancers.


Leonard B. Saltz, MD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 13, 2015 10:32 AM

1.  I would favor adjuvant therapy for such a presentation. While we routinely would want to know the mismatch repair protein status (or microsattelite instability status) of this young patient with stage II colon cancer, data from the N0147 trial indicate that dMMR is actually a poor prognostic indicator in left sided tumors (as opposed to it being a favorble prognositic indicator in right sided tumors) so I don't think it would impact on my decision here. This tumor is T4, perforated, and obstructed, which would be risk factors enough to justify adjuvant treatment. If it is either porrly differentiated or has lymphovascular or perineural invasion, that would make me worry that much more.

2.  As far as choice of adjuvant therapy, I would at the least favor use of a fluorpyrimidine for six months, but given the large number of risk factors I would lean towards adding oxaliplatin and treating with FOLFOX or CapeOx. For "high risk" stage II's with fewer risk facotrs I would often lean towards a fluorpyrimidine alone.

3. Now that the patient has metastatic disease, his tumor should be genotyped for RAS and BRAF mutation status. These would not be indicated in stage II disease, but now that he has stage IV disease they are needed for determining whether an anti-EGFR monoclonal would be part of the treatment continuum for his metastatic disease. The peritoneal pattern of spread makes me more worried about a possible BRAF mutation.


Thomas J. George, MD, FACP
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 15, 2015 12:10 PM

I agree completely with Dr. Saltz's comments on the justification for considering adjuvant therapy initially in this "high risk" patient.  

In addition to his comments, there is sometimes a role for considering Oncotype DX for stage II colorectal cancer adjuvant risk determination.  This SHOULD NOT be done if the patient does have dMMR (MSI-H) or if the tumor is T4, as both of these variables were independent predictors of risk in the studies leading to Oncotype Dx approval.  So, for this particular case, I would want to know the MSI status first and would NOT use Oncotype DX given the high-risk T4 pathologic tumor stage.  However, I put it out there for consideration as part of a comprehensive discussion in managing stage II patients with resected colorectal cancer.

Mayer Gorbaty, MD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 17, 2015 2:13 PM

1.  Thank you for the comment about  MMR testing.  In the presence of T4N0 disease does the MMR results influence your recommendation for adjuvant therapy?  eg if this had been a right sided mucinous lesion, T4N0, no obstruction and no perforation, and had tested MSI high would you then hold off on recommending adjuvant therapy?  Does T4 essentially trump MSI status?

2. If this lung lesion turns out to be benign and her recurrence is limited to the peritoneum- is there a place for intraperitineal treatment eg cytoreduction with HIPC?  If yes would you do so upfront or treat with systemic therapy,  restage and then consider consolidating with the local therapy?


Chanjuan Shi
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 14, 2015 10:18 AM

It looks like the patient has diffuse peritoneal carcinomatosis. So it is stage IV.


Anis Toumeh, MD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 14, 2015 5:49 PM

Sorry did not pay attention to the peritoneal carcinomatosis. 


1- I Would have considered adjuvant therapy giving the presentation with perforation/ acute abdomen. I wouldn't give oxaliplatin for stage II disease. Only 5-FU based ( Data is inconclusive for stage II disease ). And although the data for MMR from N0147 was suggestive of interaction between MMR status and site, one should keep in mind that the patient population was those with stage III and not stage II disease. 

2- For the metastatic disease now, would test for extended RAS mutations, BRAF ( if a lab that does the extended testing is available as the extended testing isn't yet approved by the FDA or widely practiced  ) for future treatments plans. 



Glenn Jesus Shamdas, MD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 16, 2015 9:50 AM

Let's assume tumor is BRAF positive and RAS wild; would this preclude use of anti-EGFR Abs? I realize data is controversial and some recommend combos of FOLFOXIRI type to treat these patients with inherent poorer prognosis....any thoughts ?


Helmy M. Guirgis, MD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 16, 2015 3:04 PM

Unless contraindicated, FOLFOX with Bevacizumab ia an expedient and reasonable option.


Jan A. Nowak, MD, PhD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 18, 2015 11:41 AM

Course Faculty Response

The tumor stage is determined by the traditional gross and microscopic features of the tumor.  For stage II tumors where chemotherapy is typically not a consideration, molecular testing of the tumor specifically for therapy selection is not indicated, in general. Nevertheless, evaluation of the tumor for mismatch repair deficiency (dMMR) as determined by immunohistochemistry or microsatellite instability testing (MSI) should be performed. Although the there is no indication in the patient’s personal and family histories of Lynch syndrome associated cancers, the mucinous histology in a patient less than 60 yrs old is a feature that in itself should prompt further testing (Umar, et al, 2004, Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability, J Natl Cancer Inst 96:261-268).  More recent recommendations from EGAPP (Genet Med 2009, 11(1)35-41) advocate testing all newly identified colorectal tumor for MMR deficiency for the purpose of identifying potential Lynch syndrome patients. Fifteen to 20% of colorectal tumors with display defective MMR. Approximately 3-4% of all colorectal cancers are associated with Lynch syndrome.

MMR status of the tumor also carries prognostic significance. Numerous studies have established that patients with tumors demonstrating dMMR (MSI-H) have a better prognosis than those with tumors that do not. (Guasadisegni, et al, 2010, Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of CRC survival data, Eur J Cancer 46:2788-2798).  In addition, it is generally agreed that dMMR tumors do not respond to 5FU chemotherapy.  Consequently, knowing the MMR status may weigh in the decision to recommend post-operative chemotherapy for a high risk stage II patient (or a low risk stage III patient), and in the choice of therapy, specifically avoiding 5FU only regimens.

If the tumor does display dMMR, then further evaluation for possible Lynch syndrome is appropriate.  In addition to obtaining a thorough family history, the tumor could be evaluated for methylation of the MLH1 gene promoter.  MLH1 promoter methylation is responsible for epigenetic silencing of the MLH1 gene and is responsible for the majority of non-Lynch syndrome dMMR colon cancers and its presence essentially excludes Lynch syndrome.

An alternative, surrogate test for MLH1 promoter methylation is BRAF testing: BRAF mutations are tightly linked to MLH1 promoter methylation.  BRAF mutations occur in approximately 30% of dMMR tumors.  The residual risk for Lynch syndrome in patients whose tumors are dMMR and BRAF normal is about 40%.  Those patients are candidates for formal genetic counseling and Lynch syndrome specific gene testing.


Emily Chan, MD, PhD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 18, 2015 11:44 AM

Course Faculty Response

This patient had a high risk stage II sigmoid cancer with a lung lesion of uncertain etiology.  His high risk features include tumor perforation.  Elevated CEA is also deemed a high risk feature by some although in this patient, his sarcoidosis can impact his CEA level as well.  While adjuvant therapy is not routinely recommended in stage II disease, in this patient with high risk stage II disease , I would recommend six months of adjuvant FOLFOX chemotherapy once he has recovered from his surgery and sepsis.  However, I would repeat his C/A/P CT scan prior to the start of chemotherapy to reassess the lung lesion and the abdomen given the perforation.  If there has been growth, then the concern for metastatic disease is increased and would change the goals and recommendations of therapy.

If this patient had significant pre-existing neuropathy precluding the use of oxaliplatin, then it would be important to know the MSI status as there is data showing that stage II MSI high tumors do not benefit from adjuvant fluorouracil-based chemotherapy.  Hence, they should not be offered 5-fluorouracil only adjuvant therapy.  However, they may derive benefit from adjuvant oxaliplatin and fluoropyridine chemotherapy. 


ASCO University
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 18, 2015 11:48 AM

Patient Case Update

How tissue was acquired/preserved: Formalin-fixed, paraffin-embedded tumor from surgical resection specimen was used for molecular testing.  Tissue was fixed in formalin for 24 hours, then processed for routine histology.  Unstained slides were macrodissected to enrich tumor cellularity for molecular testing. 

Testing Platform/Molecular Profiling

  • MSI testing was performed by PCR using primers specific for 5 mononucleotide loci (NR-21, NR-24, BAT-25, BAT-26, Mono-27).The tumor was microsatellite stable.
  • Mutational testing for KRAS, BRAF, PIK3CA, SMAD4, PTEN, AKT1 and NRAS was performed using PCR-based assays.  The tumor was positive for BRAF V600E mutation and the PIK3CA H1047R mutation and wild type for other mutations tested.  

Treatments initiated: adjuvant FOLFOX x 6 months

ASCO University
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 18, 2015 11:50 AM

Discussion Questions

  1. What therapy would you choose at this time with this added information?
  2. Is there any additional testing you would want at this time?



Jan A. Nowak, MD, PhD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 22, 2015 10:11 AM

Course Faculty Response

There are two methods for determining MMR status of tumors: immunohistochemistry (IHC) and microsatellite instability (MSI) testing.  IHC for MMR is dependent on antibodies specific for the four primary proteins required for functional mis-match repair: MHL1, MSH2, MSH6 and PMS2.  These proteins are expressed in normal colonic epithelial cells. The absence of one or more of these proteins as determined by IHC in a tumor indicates MMR deficiency due to mutation (e.g. Lynch Syndrome) or epigenetic silencing (e.g. MLH1 promoter methylation).

MSI testing evaluates the fidelity of DNA replication in tumor cells by examining repeat sequences, i.e. microsatellite DNAs.  A consensus conference in 2004 recommended using 5 specific mono-nucleotide repeat microsatellite loci for this purpose.  By convention, tumors displaying infidelity, or instability, for two or more loci are designated MSI-H for high frequency microsatellite instability.  Those with no instability are called microsatellite stable (MSS).  Tumors with instability at only one locus are classified microsatellite low (MSI-L). MSI-L tumors have behavior identical to MSS tumors.

Both methodologies can be performed on formalin fixed, paraffin embedded tissue.  Well validated, properly controlled IHC assays have a sensitivity of approximately 90% for identifying potential Lynch syndrome patients. Similarly, MSI testing has a sensitivity of about 90-95% for detecting Lynch syndrome patients. The sensitivities for recognizing sporadic dMMR is almost certainly higher, but optimal sensitivity requires both methods, a practice adopted by some institutions.

The potential introduction of anti EGFR directed monoclonal therapy (e.g. cetuximab) requires evaluation of the tumor for mutations in KRAS and NRAS.  Since 2008, retrospective and prospective studies have repeatedly demonstrated that tumors bearing mutations in KRAS codons 12 or 13 are less likely to respond to those therapies, presumably due to downstream constitutive activation of a MAPK signaling pathway by the KRAS mutation. Approximately 35-40% of all CRCs have KRAS codon 12 or 13 mutations.  More recently, the spectrum of mutations associated with lack of response to EGFR targeted therapies has been expanded to include less common mutations in KRAS (codons 59, 61, 117, and 146) and in NRAS (codons 12, 13, 59, 61, 117, and 146), the panel of mutations colloquially referred to “expanded” or “extended” RAS testing.  This addition adds another 10-15% of tumors which are predicted to not be responsive to the EGFR targeted monoclonal antibody therapies.

Approximately 10-12% of CRCs have BRAF mutations, most often the BRAF V600E mutation.  BRAF mutations are generally mutually exclusive with KRAS codon 12 or 13 mutations although rare double mutations have been reported. In addition to having utility in evaluating dMMR tumors for potential Lynch syndrome risk, BRAF status also carries significant prognostic weight.  The tumor stage and MMR context, however, are critical to understanding the impact of BRAF mutation on patient survival.   While studies including early stage disease indicate better survival for MSI-H tumor patients. (Lochhead, et al, 2013, Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication, JNCI 105:1151-1156), that benefit is apparently lost in patients with MSI-H and BRAF mutant metastatic tumors (Tran, et al, 2011, Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer, Cancer 117:4623-4632).


Emily Chan, MD, PhD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 22, 2015 10:23 AM

Course Faculty Response

This patient manifested metastatic disease fairly quickly after the completion of adjuvant FOLFOX chemotherapy.  Therefore, he should get an irinotecan based chemotherapy with a biologic at this time.  CALGB/SWOG 80405 showed that either bevacizumab or cetuximab can be used with chemotherapy in the first line setting in RAS wildtype metastatic colorectal cancer.

BRAF mutated colon cancer portends a poor prognosis but does not preclude benefit from oxaliplatin or irinotecan chemotherapy (Richman et al., JCO 2009).  Unfortunately, BRAF inhibitor monotherapy in colorectal cancer has not yielded the impressive responses seen in melanoma (Kopetz et al, ASCO 2010).  Prahallad, et al., showed that the limited response to BRAF monotherapy is because BRAF inhibition results in rapid feedback activation of EGFR, thus supporting continued proliferation.

More recently, BRAF inhibitor combination therapy has shown promising preliminary activity.  Yaeger et al., 2015, showed that dual inhibition of BRAF and EGFR with the combination of vemurafenib and panitumumab resulted in tumor regressions in 10 of 12 evaluable patients with partial responses in two patients.  Hong et al., 2014, conducted a phase IB trial of vemurafenib, irinotecan, and cetuximab resulting in partial responses in four of five evaluable patients.  These results led to the development of S1406, a phase II trial of irinotecan and cetuximab with or without vemurafenib in BRAF mutant metastatic colorectal cancer with crossover allowed at progression.  Preliminary results of a trial of the BRAF inhibitior LGX818 in combination with cetuximab with or without BYL719, an α specific PI3K inhibitor was reported in 2014 and showed three partial responses in 18 treated subjects (Van Geel, ASCO 2014).  Other trials have combined BRAF inhibitors with MEK inhibition.

Given the poor prognosis of BRAF mutated metastatic colon cancer, my preference would be to enroll the patient in a BRAF combination trial if he were eligible and interested.  In the absence of an available clinical trial, I would treat with an irinotecan based regimen and bevacizumab.


Jan A. Nowak, MD, PhD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 27, 2015 9:31 AM

Course Faculty Summary

Thank you everyone for the discussion. Below are my take away points based off of the available information:

  1. The EGAPP study determined that there was sufficient evidence to warrant testing all newly identified CRC patients for potential Lynch syndrome.
  2. Tumor MMR status is important for prognosis, choice of therapy, and evaluation for potential Lynch syndrome. Hence, it is reasonable to test all newly identified CRCs for MMR.  
  3. IHC and MSI are both suitable for MMR evaluation, but both methods will not detect some cases of Lynch syndrome. Optimal sensitivity requires both methods.
  4. Use of EGFR targeted monoclonal antibody therapies requires “expanded” RAS testing.
  5. BRAF mutation status can be used to evaluate MSI-H tumors for potential Lynch syndrome risk.
  6. The prognostic significance of BRAF mutation is significant for both MSS and MSI-H tumor patients.
  7. Understanding MMR and BRAF status may influence therapeutic decision making.



Emily Chan, MD, PhD
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 27, 2015 9:35 AM

Course Faculty Summary

Thank you everyone for the interest in this discussion.  These are my take away points based off of the information:

  1. We do not routinely recommend adjuvant chemotherapy in stage II disease but it should be considered in high risk stage II disease.
  2. Fluoropyrimidine monotherapy in the adjuvant setting should not be used in MSI-H stage II colon cancer.
  3. Adjuvant chemotherapy should be started as soon as the patient has recovered adequately from surgery.  Delays in initiation of adjuvant therapy impact clinical outcomes.
  4. Tumor genotyping in early stage disease should not be routinely done as it will not change management.
  5. Tumor RAS status should be ascertained for all metastatic colorectal cancer patients who are candidates for palliative chemotherapy.
  6. B-RAF mutation portends a poor prognosis in metastatic colorectal cancer.  These patients should be encouraged to enroll in clinical trials with combination therapy with a BRAF inhibitor.


ASCO University
Re: Colorectal Cancer (May 2015): Molecular Oncology Tumor Boards
May 27, 2015 9:47 AM

Thank you to Drs. Chan and Nowak for leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim credit on ASCO University by accessing this link.

Please check back in mid-June for a new case in this series related to Ovarian Cancer.