All colorectal cancer patients require germline testing at diagnosis and somatic testing at advanced disease diagnosis

Technological advances are transforming our understanding of cancer, accelerating the evolution of new treatment approaches. In the past decades, researchers deploying new techniques for analyzing DNA have extended our knowledge of inherited genetic abnormalities that can predispose a person to develop colorectal and other cancers. 

Those insights have led to specific strategies to manage and minimize risk for affected individuals and their family members. Today, these insights permit us to decipher the heterogeneity of colorectal and other cancers based upon the identification of the genetic abnormalities that drive the development and progression of an individual patient’s cancer. 

The genetic fingerprinting of individual tumors has fueled the development of targeted therapies and informed their appropriate deployment for the management of individual patients. 

Recently, Drs. Andrea Cercek, Luis Diaz, and their colleagues at Memorial Sloan Kettering Cancer Center reported that all 14 patients with rectal cancer who had a genetic abnormality predisposing them to develop cancer and who were treated in a clinical trial had complete remissions of their disease when given a drug that permitted their immune systems to recognize and destroy their cancers (The Cancer Letter, June 10, 2022).

These patients achieved remission without undergoing chemotherapy, radiation, or surgery. While these results are preliminary, they are unprecedented. Congratulations to this research team and their patients who are the catalyst that led us to write this opinion piece!  

As the individuals writing this article, we were brought together through our involvement in the patient advocacy community. Our advocacy group, “Fight Colorectal Cancer,” is a coalition of patients, family members, cancer care providers, cancer researchers, representatives from the drug and device industry, and donors with a concordant interest in improving outcomes for individuals with colorectal cancer. 

All of us believe that now is the time to deploy genetic testing—universally and equitably—for individualizing the assessment of inherited colorectal cancer susceptibility and for individualizing those patients’ care. 

Consider the stories of two patients, Wenora and Daniele.

Both were ultimately found to have Lynch Syndrome, a genetic abnormality predisposing to the development of colorectal and other cancers. They have chosen to tell their stories here to illustrate why everyone diagnosed with colorectal cancer should get germline testing, and somatic gene testing when they manifest advanced disease.

Wenora Johnson’s story

In 2011, at age 44, Wenora was diagnosed with stage IIIB colorectal cancer and received the standard treatment of surgery to remove part of her colon, followed by chemotherapy. 

While her oncologist suspected she might have Lynch Syndrome due to a family history of cancer, it wasn’t until 2015 when genetic testing was completed. 

Diagnosed as Lynch Syndrome-positive, with an MSH2 mutation that confers a high risk of endometrial cancer, Wenora underwent a preventive total hysterectomy. 

The pathology report revealed that she had an unsuspected stage 1A endometrial cancer. She subsequently had an additional diagnosis of a basal cell skin cancer in 2017, and today has no evidence of any residual cancer.

Currently, Wenora’s brother suffers from stage IV colorectal cancer. Despite knowing his sister’s history, he didn’t have genetic testing done to determine whether he has LS. In his current circumstance, Wenora feels that her brother could benefit from genetic testing on his tumor now to inform the management of his advanced cancer. 

That testing could allow the use of biomarkers and targeted therapies in his treatment plan. Wenora states that she doesn’t just advocate for herself, but for her family and for others who can’t speak up or understand new or existing treatment options related to universal genetic testing. 

She hopes to bridge the gap between patients, medical care providers, industry, and the advocacy community, so that they can all work together to improve patient lives. 

As a Lynch Syndrome patient, she realizes that genetic testing has saved her life and encourages universal genetic testing, which may uncover inherited genetic mutations, and could individualize cancer therapies, and improve survival for colorectal cancer patients. As a member of a minority community, Wenora believes that it is imperative that these technologies are accessible to all individuals with colorectal cancer.

Danielle Ripley-Burgess’s story

Immediately after diagnosing Danielle with stage III CRC when she was 17 years old, her medical team suspected Lynch Syndrome. They ordered a multigene-panel test on her tumor. 

Indeed, her tumor manifested a genetic abnormality. The team then sent her blood for analysis to see if the genetic abnormality was present in her DNA. 

When it came to her DNA, the report said that Danielle had a variant genetic abnormality of unknown significance. Suspicious of Lynch Syndrome, doctors guided her family to genetic counseling. 

Although she didn’t have any first-degree relatives with Lynch-related cancers that made a hereditary syndrome obvious, her mother got tested. The test was negative. 

Danielle faced colon resection and ovarian suspension surgeries, followed by FOLFIRI chemotherapy and pelvic radiation. Following treatment, she has been in complete remission and remains in complete remission.

As Danielle stepped into survivorship, she was encouraged to get a colonoscopy every three years, a recommendation which she has followed religiously. Eight years after her initial diagnoses, at age 25, a follow-up colonoscopy revealed a second tumor. Danielle underwent a subtotal colectomy to remove the cancer and the pathology examination indicated it was caught early at stage I. 

Genetic testing was ordered again, and the report came back reading the same as the first: The tumor harbored a genetic variant of unknown significance. 

Suspicions that she carried Lynch Syndrome increased further after Danielle’s second cancer. Although genetic testing at that time didn’t conclude that she carried Lynch Syndrome, practitioners treated her as though she did, and fortunately, her insurance covered all prescribed tests and procedures. 

Danielle underwent a hysterectomy and oophorectomy, her follow-up colonoscopy became annual, and she began undergoing upper endoscopies every three years. She also began having dermatology visits and annual tests to look for cancer cells in the urine. 

Four years following her second diagnosis, she received an urgent call from her geneticist. After the results of additional research became known, the laboratory that had found the genetic variant noted in her DNA informed her that the variant was now considered pathogenic. She officially was classified as having Lynch Syndrome. 

Danielle felt fortunate that her medical team had already acted on their suspicions and treated her as a Lynch Syndrome patient. 

Follow-up colonoscopies had already begun finding and removing polyps each year. The diagnoses impacted her immediate family. Her father was urged to get tested as well, but assumptions that it would be positive were proven wrong. He was negative.

Danielle was found to be the first person in her family to carry the Lynch Syndrome mutation. This knowledge released her mother, father, and brother from the high-risk screening schedule they had been following. Also, it confirmed Danielle’s decision to undergo preventive surgery to end her fertility, and it illuminated the importance of her annual colonoscopy and other follow-up tests. 

Had she been diagnosed today, as opposed to 21 years ago, Danielle could have been a candidate for a immune therapy with a PD-1 inhibitor, which could have put her life and the lives of her family members on a different path. 

Danielle is grateful for her medical team for ordering genetic testing at the time of both of her cancer occurrences, as well as to the people at the laboratory who had stored her data and communicated with her when the gene variant that they found was reclassified as indicating that she had Lynch Syndrome. 

She credits these caregivers for the remission she continues to experience today.

The case for universal testing

In 2021, 149,000 individuals were diagnosed with colorectal cancer (CRC) in the U.S., and 53,000 Americans died of the disease making it the second most common cancer and cancer killer.¹

According to projections, by 2030, CRC will be the leading cause of cancer deaths in Americans under the age of 50. While the overall incidence is decreasing, this trend is for older patients and the incidence rates in young onset patients (<50 years old) is rising. 

The screening technologies, guidelines for screening, and treatment options for people with CRC have evolved rapidly in the last two decades. 

One area of research that is changing with the greatest rapidity relates to genomic testing.

Multiple platforms for dissecting the individual genetic drivers of cancer are now approved by the FDA for use in patients and cancers of all types. 

It’s unknown what proportion of patients with CRC now receive multi-gene panel testing (MGPT). 

This testing is sometimes performed at the time of diagnosis to test the patient’s DNA for a heritable cancer predisposition syndrome (germline testing). 

Also, MGPT is often performed on a patient’s tumor in the setting of metastatic disease to identify if a tumor has driver mutations that may make it either amenable or resistant to treatment with targeted therapies (somatic testing). 

Mutations in tumors can be inherited or acquired, and the determination of whether a mutation in a tumor is inherited involves doing a second genetic test on the patient’s (as opposed to the tumor’s) DNA (usually using blood, saliva, or rarely for patients with hematologic malignancies, skin cells called fibroblasts). 

The National Comprehensive Cancer Network (NCCN) has recommended testing for germline mutations for all patients diagnosed with epithelial ovarian/fallopian tube cancers (prevalence 18.1-23.6%), high-grade prostate cancers (prevalence 11.8%), and pancreatic adenocarcinomas (prevalence 3.8-8.4%) for the purpose of identifying heritable cancer risk for many years.²

Data suggest that 9.9-15.5% of patients with CRC harbor pathogenic or likely pathogenic germline mutations.³ Those associated with Lynch Syndrome account for ~3-4% of CRC cases.^4,5 

Other mutations associated with heritable CRC predisposition syndromes include CHEK2, MUTYH, APC, TP53, BMPR1A, SMAD4, POLE, POLD1, AXIN2, NTHL1, MSH3, MLH3, and STK11 mutations. In addition, multiple studies have identified mutations in cancer susceptibility genes that are not known to cause CRC (e.g. BRCA1, BRCA2, PALB2, etc.) among CRC patients but are important for the patient and their family members nonetheless. 

Multiple other guideline groups have rendered opinions regarding germline MGPT. These “expert recommendations” often change on a yearly basis and can be contradictory leading to confusion on the parts of both providers and patients, particularly among individuals from both groups who are not themselves experts in the interpretation of genetic data.^6,7,8

Lynch Syndrome

There is a growing awareness among medical practitioners and the public that individuals with LS have greatly elevated risk of developing cancers that can arise in a multitude of organs. 

LS is characterized by the existence of a pathogenic variant in one of the mismatch repair genes. When functioning normally these genes produce proteins that work together to correct replication errors in DNA that inevitably occur during cell division. 

When cells divide, the DNA double helices unravel and are replicated to permit the formation of two daughter cells each with double strands of DNA derived from a single DNA copy contributed to the new cells from the parent cell. Tumors with defective mismatch repair usually acquire microsatellite instability and are classified as MSI-H.⁹

Implications of a diagnosis of LS for cancer screening

The discovery of LS in a cancer patient has powerful implications regarding their risk of future cancers and for their medical management, including prevention strategies, screening, surveillance, the identification of at-risk relatives and the treatment of their cancers as illustrated by both Wenora’s and Danielle’s cases. 

This helps to determine the age when cancer screening should be indicated, which organs need to be screened, and how often those screenings are to be performed in individuals with LS.^10,11,12

Given its autosomal dominant inheritance pattern, the first-degree relatives of a person with colorectal cancer or another cancer associated with LS have a 50% chance that they also have LS. If 3% of the 149,000 individuals with CRC diagnosed in 2021 have LS, that means 4,470 cases arose as a result.¹³ 

Studies done by investigators at the Ohio State University’s Ohio Colon Cancer Prevention Initiative found an average of three affected relatives per index LS case.¹⁴ 

This finding suggests that 17,880 additional individuals with LS can be identified by screening all the 2021 CRC cases diagnosed in the U.S. for LS and offering cascade testing to the at-risk relatives of those who test positive. 

Interventions to reduce cancer risk and to manage LS-associated cancers

Data from randomized clinical trials also indicate that daily ingestion of aspirin can reduce the risk of CRC in individuals with LS.¹⁵ 

Risk-reducing surgeries, such as hysterectomy and bilateral salpingo-oophorectomy (removal of the ovaries and fallopian tubes) to reduce the risk of developing uterine and ovarian cancers or total colectomy which is often recommended at the time of diagnosis of a CRC due to the high risk for metachronous (simultaneous) tumors are additional interventions to be considered.¹⁶ 

Importantly, the presence of LS has therapeutic implications in treating cancers, as MSI-H tumors are more likely to respond to immuno-oncology agents that target the PD-1 or PD-L1 pathways, and some data suggest that LS-associated tumors have differential resistance/sensitivity to chemotherapy agents such as 5-fluorouracil.^17,18 

Previously, we referenced the preliminary report by Cercek and colleagues.  In that clinical trial, all 14 patients with MSI-H rectal cancers enrolled to date were treated for six months with a PD-1 inhibitor. All had a complete remission of their disease without the need for chemotherapy, radiation, or surgery. 

Assuming that these preliminary data are confirmed, this would be a compelling reason to test all newly-diagnosed rectal cancer patients before treatment to discern if their tumors are MSI-H.¹⁹ Studies of PD-1 inhibitors as adjuvant therapy for stage III colon cancer are underway, with unknown outcomes at this time.²⁰ 

New NCCN guideline

As noted, LS is one of multiple hereditary cancer syndromes that can be identified using MGPT. NCCN guidelines published in 2017 recommend germline testing for all patients with CRC diagnosed under the age of 50. 

The 2022 update of these guidelines was revised to recommend that clinicians consider ordering MGPT in all CRC cases, but it falls short of recommending universal MGPT for all individuals diagnosed with CRC. 

This guidance is in place despite the finding from a Harvard University study that age, family history of CRC, and personal history of cancer were not predictive of which patients with CRC (~7%) would be found to have inherited cancer susceptibility syndromes other than LS.²¹ 

In the past, the American Society of Clinical Oncology and other deliberative bodies have considered a 10% threshold of pathologi genetic variants (PGVs) to be high enough to justify a recommendation for universal MGPT. It appears that CRC exceeds this threshold, with recent studies suggesting the prevalence of pathogenic variants in cancer susceptibility genes is ~16% in unselected colorectal cancer patients.¹⁴ 

Disparities in access to and the use of both genetic counselling and MGPT have been identified in studies conducted in U.S. populations with breast and colorectal cancers, with Black patients being less likely to be offered or to take advantage of these test and services. Universal germline testing could be a means of minimizing such disparities.^22,23,24  

Somatic MGPT is also relevant for discerning which patients with CRC have druggable target mutations or mutations such as RAS mutations that indicate resistance to certain targeted drugs (in this circumstance RAS mutations confer resistance to monoclonal antibodies that target the epidermal growth factor receptor [EGFR]). 

MGPT tumor testing can identify actionable mutations which can be used to tailor treatment today. These include RAS, BRAF, MSI, ALK, NTRK fusions, FGFR fusions, ERBB2, and others. The American Society of Clinical Oncology (ASCO) convenes expert panels to assess when new technologies are sufficiently well study to determine when and how they should be deployed in clinical practice. 

On June 19, an ASCO expert panel reported a provisional clinical opinion in the Journal of Clinical Oncology stating that “patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease.”²⁵ 

Patients with colorectal cancer clearly fit these criteria for MGPT. 

Challenges

The adoption of universal germline and somatic MGPT screening for colorectal cancer would demand changes in the way medicine is practiced in the U.S. 

It would lead to a dramatic increase in testing, the need to accurately interpret the results, and equitable access to follow-up care. It is estimated that there would be 80,000 incremental germline tests done per year in the U.S. 

It would also be prudent to test the many CRC survivors who never underwent genetic testing and who would be eligible for testing as would the relatives of those who test positive for LS. This would strain currently constrained resources for genetic counselling. However, educational efforts that improve the competence of other providers that rely on templated approaches have been implemented successfully.^26,27 

While the cost of the MGPT is coming down each year, the costs of performing 80,000 additional tests remain significant. Models of quality adjusted life years saved by implementation of enhanced screening and treatment favor the cost effectiveness of this approach. 

To comply with the recommendations of the ASCO expert panel, additional somatic testing would need to be performed in patients with advanced disease.

Conclusion

We believe that the time for universal germline screening of all individuals diagnosed with CRC in the U.S. and for universal somatic screening of all individuals with advanced CRC is now. The new NCCN guidelines, the study by Cercek, and colleagues, and the new ASCO guidelines for advance disease fuel this argument. 

The incidence rates, opportunities for cancer prevention, and ability to tailor therapy all depend on taking advantage of the genetic data we now have at our fingertips. 

Every CRC patient deserves to benefit from these discoveries.

References:

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