Appeal type: Medical necessity
Decision: Upheld

Diagnosis: Family history of cancer
Treatment: Hereditary Cancer Test (81479)

The insurer denied the Hereditary Cancer Test (81479).
The denial is upheld.

The patient is a female with no personal history of cancer.  Her mother was diagnosed with ovarian cancer. She was tested for germline mutations in breast cancer one (BRCA1) and breast cancer two (BRCA2) (as indicated on the letter of medical necessity submitted) and this testing was negative. 

The patient underwent BRACAnalysis with Myriad myRisk Update testing. This was denied by the plan as not being medically necessary. It was judged as not medically necessary as the patient's mother was previously tested. As such, the patient should only have been tested for the specific mutation found in the mother (if any). 

This was appealed by Myriad Genetics as being supported by the National Comprehensive Cancer Network (NCCN) Guidelines. It did not address that the provided records indicate that the patient's mother was tested for germline breast cancer one (BRCA1) and breast cancer two (BRCA2) mutation and this testing was negative.

No, the proposed testing was not medically necessary.
The patient has no history of cancer. Her mother had had ovarian cancer diagnosed. The patient's mother was tested for germline mutations in breast cancer one (BRCA1) and breast cancer two (BRCA2) (as indicated on the letter of medical necessity submitted) and this testing was negative. 

The patient underwent BRACAnalysis with Myriad myRisk Update testing. This is a next-generation panel test for hereditary cancer susceptibility that sequences the following genes:
BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH Biallelic, MUTYH Monoallelic, CDKN2A (p16INK4a), CDKN2A (p14ARF), CDK4, TP53, PTEN, STK11, CDH1, BMPR1A, SMAD4, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD51C, RAD51D, POLD1, POLE, GREM1, HOXB13, AXIN2, GALNT12, RPS20, RNF43, NTHL1 Biallelic, NTHL1 Monoallelic, MSH3 Biallelic, MSH3 Monoallelic (BRACAnalysis).

There were no other members of the patient's family with cancer. The patient's mother did not have breast cancer one (BRCA1) or breast cancer two (BRCA2) mutations. There was no indication for performing breast cancer one (BRCA1) and breast cancer two (BRCA2) mutations in this patient (NCCN Breast Genetics, page CRIT-2; Moyer). 

The myRisk Update test is a hereditary cancer mutation panel test. There are several problems with such broad hereditary mutation panel testing. 

Mutations in many of the genes have caused significant physical/developmental abnormalities (APC, PTEN, and others) such that carriers of known deleterious mutations can be identified by physical findings. Patients without the classical physical findings of the associated syndromes are highly unlikely to carry mutations in these genes, and testing for mutations in these genes is not indicated.

Mutations in many of the genes sequenced (SMAD4, and others) are not associated with a sufficient increased risk of cancer such that there are clear recommendations for effective screening and/or cancer prevention strategies. 

Sequencing large panels of genes is highly likely to find "variants of undetermined significance" (VUS). Being told that "you have a mutation in a gene, but we don't know whether it may increase your risk of cancer" will cause unnecessary anxiety for the patient. 

If a mutation in a well-established cancer predisposition gene is found but is not a known deleterious mutation, and is thought "in silico" to be deleterious (but in fact may not be deleterious), the patient may be erroneously informed that they have a cancer predisposition syndrome and act on this information to the detriment of their health and well-being. 

For all of these reasons the utility of next-generation sequencing panels for cancer susceptibility testing is unproven and is not medically necessary. 

The mutation panel test was not medically necessary.

Yes, the health plan acted reasonably, with sound medical judgment and in the best interest of the patient.
Given the absence of breast cancer one (BRCA1) and breast cancer two (BRCA2) mutations in the patient's mother who had ovarian cancer and the absence of any other family history of cancer, it was highly unlikely that the patient's family contains any hereditary cancer mutations. 

In testing this many genes, the most likely outcome was that variants of undetermined significance (VUS) would be detected. These findings - which do not help the management of the patient - often cause increased anxiety in the patient. Given the absence of any indication to perform the testing, the risk of finding variants of undetermined significance that would just cause anxiety for the patient causes the expected outcome of the testing to have a negative impact on the patient's physical and mental health.

Analysis of the utility of next-generation sequencing panels for cancer susceptibility testing has not been uniformly positive. One hundred ninety-eight women who had breast cancer one/two (BRCA 1/2) mutation testing had an additional 40 genes known to be associated with hereditary cancer mutations sequenced (Kurian). Participants carried an average of 2.1 variants of uncertain significance among 42 genes and only one high-penetrance mutation was identified (a Lynch syndrome mutation). This one patient's history otherwise met expert recommendations for Lynch syndrome testing (blind testing of the panel of genes was not supported by this finding). Although 16 potentially pathogenic mutations in other genes were identified, the conclusions of the authors were that, "Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility."

The utility of next-generation sequencing panels for cancer susceptibility testing, such as the Integrated BRACAnalysis with Myriad myRisk Cancer Panel test, is unproven. Reviews of gene panel testing for inherited cancer susceptibility conclude that this testing is unproven:
"Regarding further development of multi gene panel testing, more research is required to establish both the optimal care of patients with cancer (specific treatments like PARP inhibitors) and the management of unaffected individuals (chemoprevention and/or prophylactic surgeries). Early detection in these patients as well as prophylactic measures will significantly increase the chance of survival. Therefore, multi gene panel testing is not yet ready to be used outside clear guidelines. In conclusion, studies on additional cohorts will be needed to better define the real prevalence, penetrance and the variants of these genes, as well as to describe clear evidence-based guidelines for these patients."
(Catana)

"New techniques, such as next-generation sequencing, allow the simultaneous analysis of multiple genes in a cost-effective way. As a logical consequence, gene panel testing is entering clinical practice with the promise of personalized care. We however advocate that gene panel testing is not ready for non-specialist clinical use, as it generates many variants of unknown significance and includes more genes than are presently considered clinically useful."
(van Marcke)