Colon Cancer (May 2017): Molecular Oncology Tumor Board

ASCO University
May 10, 2017 8:23 AM

Participant 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. Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

This month's topic is lead by Drs. Thomas George, MD, FACP (Medical Oncologist, University of Florida Health Cancer Center) and Stuti Shroff, MD, PhD (Pathologist, University of Pennsylvania Perelman School of Medicine).

Participants are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

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Please click below for supplemental resources related to the presented case:

 

JCO Podcast (ASCO members): Prevalence of Germline Mutations in Individuals with Colorectal Cancer as Determined Using a Multi-Gene Panel Test

List of References

Comments

14506

ASCO University
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 10, 2017 8:33 AM

Patient Case

Patient History: A 51-year-old woman with a remote history of cholecystectomy noted progressive fatigue ultimately determined to be iron deficiency anemia. Colonoscopy revealed a large non-obstructing mass in the ascending colon with biopsy confirming invasive adenocarcinoma.  There was no evidence of active bleeding. Baseline labs confirmed normal liver, kidney, and marrow function.  CEA was elevated at 35ng/mL.

Pathology: Histopathology confirmed a moderately differentiated invasive adenocarcinoma (Pictures 1 and 2, intermediate and high magnification, respectively). The background colon was normal. 

Picture 1: The tumor had a variegated morphology and showed areas of mucinous differentiation (image provided by Dr. Stuti Shroff, MD, PhD).

Picture 2: At higher magnification, the invasive adenocarcinoma had this appearance with prominent intratumoral lymphocytes (yellow arrows, image provided by Dr. Stuti Shroff, MD, PhD).

Next generation sequencing (NGS) was performed and confirmed wild-type RAS (extended profile) and BRAF tumor status.

Radiology: Staging CT of the Chest, Abdomen and Pelvis with IV contrast showed thickening in the ascending colon without evidence of obstruction, consistent with the known primary tumor.  There were several mesenteric regional lymph nodes noted near the primary tumor.  At least 7 hypodense lesions were identified in the liver (bilateral involvement including the caudate) as well as two small lung nodules, all consistent with metastatic disease. 

14511

ASCO University
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 10, 2017 8:54 AM

Discussion Questions

  1. Is the location and morphology of this tumor significant clinically?
  2. Prior to NGS what additional testing could have been performed?
  3. Is one test for hereditary colon cancer better than the other?
  4. What is the role of genetic counseling for this patient?

14521

Anis Toumeh, MD
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 10, 2017 4:51 PM

Determination of MSI status and obtaining IHC panel for MLH1, MSH2, MSH6 and PMS2 will be very important, especially with a right sided colon cancer as these tumor (as opposed to left sided tumors) are more likely to have a MMR deficiency. I would also obtain a detailed family history. 

14541

Thomas J. George, MD, FACP
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 15, 2017 8:41 AM

Course Faculty Response

This relatively young patient has the unfortunate diagnosis of multifocal metastatic (stage IV) colorectal cancer (mCRC).  Despite well-established national screening guidelines (US Preventative Services Task Force, et al.), the diagnosis of CRC remains common in those greater than the age of 50.  However, there is an increasing incidence rate of CRC in those younger than 50 (Siegel et al.).  Although this patient was diagnosed after the age of 50, the premalignant condition and earlier stage of the cancer likely predated her diagnosis by a number of years.  Assessment of risk factors and family history of the younger CRC patient are critical (Lowery et al.), but family history alone is unreliable in a moderate number of patients with confirmed hereditary syndromes.  One consideration for any patient with newly diagnosed CRC is to assess for a hereditary colorectal cancer syndrome, specifically Lynch Syndrome (Stoffel et al.).  This testing can be accomplished with high reliability by testing the tumor for evidence of mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H).  Depending on the test results and in the context of the patient’s wishes, referral to genetic counseling should be strongly considered, consistent with national guidelines.

Taken together with the NGS data already obtained (extended RAS and BRAF wild-type), knowing the MMR or MSI status of the patient’s cancer is clinically important.  Notably, the extended RAS testing serves as a negative predictive factor for response to anti-epidermal growth factor receptor therapies and the BRAF status is also highly prognostic.  These molecular data results should be routinely obtained on every patient with mCRC (Allegra et al.). 

14546

Stuti Shroff
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 15, 2017 8:45 AM

Course Faculty Response

The young age, right sided location, variegated morphology and mucinous differentiation of the tumor, along with prominent intratumoral lymphocytes are histologic findings highly suggestive of a miscrosatellite instability-high [MSI(H)] colorectal  adenocarcinoma (CRC, Umar et al.). The revised Bethesda guidelines were established to help identify patients with colorectal cancer who should undergo tumor testing for microsatellite instability. Due to the limited sensitivity of the Bethesda guidelines in detecting patients with Lynch syndrome, Universal screening for Lynch syndrome is currently recommended by the NCCN, EGAPP, and ASCO amongst other professional Organizations (Benson III et al., Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, and Stoffel et al.).

Defective mismatch repair (dMMR) results in instability in the number of microsatellites throughout the genome. These defects are repaired by the mismatch repair genes. If the mismatch defects are left unaltered, a high level of microsatellite instability [MSI(H)] occurs in the genome, which contributes to carcinogenesis along the microsatellite instability pathway.

An MSI(H) CRC may be of sporadic origin due to somatic epigenetic alterations (hypermethylation of the MLH1 gene promoter region), constituting 12-15% of all CRC. Alternatively, it can occur due to germline mutations in the mismatch repair genes – aka Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC), constituting 2-3% of all CRC.

There are two main screening modalities for identification of high levels of microsatellite instability within the CRC. One modality is by immunohistochemistry (IHC) and the other is by polymerase chain reaction (PCR). MSI testing by IHC evaluates for loss of expression of the four mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) in the adenocarcinoma compared to the background normal cells. MSI testing by PCR is performed with at least 5 microsatellite markers (Boland et al.). Different algorithms may be utilized by different institutions for MSI testing (Pai and Pai).

Four discrete patterns of loss of mismatch protein expression within the tumor cells by IHC have been identified. At a genomic level, MSH2 forms a heterodimer with MSH6, and MLH1 forms a heterodimer with PMS2 in the process of defective mismatch repair.  Loss of expression of MSH2 along with MSH6, MSH6 alone or PMS2 alone are indicative of germline alterations in the mismatch repair genes. These patients should be sent for genetic counseling. Loss of MLH1 along with PMS2 may be due to sporadic epigenetic or germline alterations. 

Sporadic MSI(H) CRC is most often due to epigenetic inactivation of the MLH1 gene promoter by hypermethylation. Mutation of the BRAF gene at the V600E hotspot locus in found in a majority of sporadic MSI(H) CRC with hypermethylation of the MLH1 promoter. Therefore patients with MSI(H) CRC who have a somatic BRAF V600E mutation or MLH1 gene promoter hypermethylation should not be subjected to additional germline testing or genetic counseling, as these findings exclude the possibility of Lynch syndrome.

Genetic counseling is indicated for the remainder of the patients with MSI(H) CRC with loss of MLH1 and PMS2 protein expression.  

14551

ASCO University
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 15, 2017 8:47 AM

Patient Case Update

The patient’s tumor was submitted for assessment of mismatch repair deficiency (dMMR).  Testing results confirmed a loss of MSH2 and MSH6 by immunohistochemical (IHC) staining.  The patient was referred to genetic counseling where Lynch Syndrome (MSH2 mutation) was confirmed, and family members were offered genetic testing.  You counseled her to have her younger siblings undergo screening colonoscopies and other appropriate tests in consultation with their primary care doctors.

Given the widely metastatic nature of her disease, this patient was enrolled in a clinical trial utilizing anti-programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) immunotherapies given promising results in this patient population (Le et al.).

Importantly, her 44-year-old brother followed your colonoscopy advice and was found to have a cecal adenocarcinoma without evidence of overt metastases.  His surgery was uncomplicated. Pathology revealed a moderately differentiated pT3N0 colonic adenocarcinoma confirmed to be MSI-H/dMMR.  He scheduled an appointment with you for adjuvant treatment recommendations.

14556

ASCO University
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 15, 2017 8:49 AM

Discussion Questions

  1. What other malignancies can develop in the siblings of the first patient given her diagnosis of Lynch syndrome?
  2. Are there any other clinical or molecular information needed in her brother’s case?
  3. What is your recommendation for adjuvant therapy for him?

14561

Thomas J. George, MD, FACP
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 19, 2017 7:40 AM

Course Faculty Response

The decision to test for a hereditary colon cancer syndrome in the first patient with metastatic disease set in motion a series of clinically meaningful discoveries.  The knowledge gained was used to identify a biomarker which appears to be relevant for response to immunotherapies.  Additionally, the information was successfully used to counsel the patient’s family members to obtain cancer screening studies well before they would have considered it.  While the recommendations to undergo a colonoscopy 10 years prior to the age of diagnosis of a first degree relative with CRC is standard, the identification of Lynch Syndrome was important to convey to the gastroenterologist performing the study given that flat lesions or subtle mucosal irregularities are far more common than overt polyps.  Hence the historical name for Lynch Syndrome (AKA Hereditary Non-Polyposis Colorectal Cancer).

This second patient (younger brother) was fortunate to have followed your advice and was found to have a stage IIA colon cancer.  While it is important to confirm adequate nodal sampling was performed (>12 LN) and post-op CEA has normalized, this patient has an excellent prognosis.  In the setting of stage IIA colon cancer, MSI-H patients have a 90% 5-year disease free survival with surgery alone.  Adjuvant therapy would not be recommended as both his prognosis is excellent and there is some evidence that this subtype of tumor is relatively resistant to fluoropyrimidine therapy (Kim et al. and Sargent et al.).  Active monitoring for second colorectal cancers should be initiated, genetic counseling provided and other Lynch Syndrome-associated cancer screenings should be discussed.

14566

Stuti Shroff
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 19, 2017 7:42 AM

Course Faculty Response

Patients with Lynch syndrome have a higher propensity to develop synchronous and metachronous colorectal adenocarcinoma. Other than colorectal adenocarcinomas, patients with Lynch syndrome have a higher propensity to develop malignant adenocarcinomas in the endometrium, ovary, small intestine, stomach, pancreaticobiliary tree, urinary tract and brain (gliomas).

14586

Thomas J. George, MD, FACP
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 24, 2017 7:56 AM

Course Faculty Summary

The optimal management of both metastatic and early stage colon cancer today relies heavily on molecular profiling results.  In particular, extended RAS, BRAF and mismatch repair deficiency status should routinely be obtained on all patients with colon cancer.  A positive family history or clinical features (i.e., young patient with right-sided colon cancer) alone should not drive decision making regarding testing for hereditary colon cancer syndromes as even epigenetic or acquired changes resulting in deficient DNA repair systems have different prognostic and therapeutic implications, depending on the disease stage.  Given the implications of not having this information available to guide your recommendations and the potential benefits to the patient and their families, strong consideration should be given to routine or even reflexive testing of these molecular tests as part of your routine clinical practice in the care of patients with colorectal cancer.  This is a standardized and reflexive set of data I obtain on all patients in my own clinical practice.

14591

Stuti Shroff
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 24, 2017 7:57 AM

Course Faculty Summary

At the pathology bench, every colorectal adenocarcinoma should undergo screening to evaluate for defective mismatch repair. At our institution, we use immunohistochemistry (IHC) as the screening modality of choice due to its cost-effectiveness, relatively high sensitivity (~90%) and ease of interpretation. If mismatch repair protein abnormalities are suspected based on clinical features, and these are not identified by IHC, then additional screening by PCR may be performed. Identification of the mismatch repair status of the colorectal adenocarcinoma in every individual is imperative as it has important preventive, therapeutic and prognostic implications. Involvement of the genetic counselor as and when needed should be performed to make sure that these patients are not lost to follow up. 

14596

ASCO University
Re: Colon Cancer (May 2017): Molecular Oncology Tumor Board
May 24, 2017 7:58 AM

Thank you to Drs. Shroff  and George 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 and participants can claim CME credit and 1 ABIM MOC point through ASCO University.

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

Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.