Category Archives: Genetic Therapy

Experimental: Subprotocol A (EGFR activating mutation)

Patients with EGFR activating mutation receive afatinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Given PO

Other Name: BIBW 2992

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Patients with HER2 activating mutation receive afatinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Given PO

Other Name: BIBW 2992

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Patients with MET amplification receive crizotinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Given PO

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Patients with MET exon 14 deletion receive crizotinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Given PO

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Patients with EGFR T790M or rare activating mutation receive osimertinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given PO

Patients with ALK translocation receive crizotinib PO twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Given PO

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Patients with ROS1 translocation or inversion receive crizotinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Given PO

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Patients with BRAF V600E/R/K/D mutation receive dabrafenib PO BID and trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Given PO

Undergo molecular analysis

Given PO

Patients with PIK3CA mutation without RAS mutation or PTEN loss receive taselisib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given PO

Other Name: GDC-0032

Patients with HER2 amplification >= 7 copy numbers receive pertuzumab IV over 30-60 minutes and trastuzumab emtansine IV over 30 minutes on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given IV

Given IV

Patients with mTOR mutation receive sapanisertib PO daily on days 1-28. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given PO

Patients with TSC1 or TSC2 mutation receive sapanisertib PO daily on days 1-28. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given PO

Patients with PTEN mutation or deletion and PTEN expression receive PI3K-beta inhibitor GSK2636771 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given PO

Other Name: GSK2636771

Patients with PTEN loss receive PI3K-beta inhibitor GSK2636771 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given PO

Other Name: GSK2636771

Patients with HER2 amplification receive trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given IV

Patients with BRAF fusion or BRAF non-V600 mutation receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given PO

Patients with NF1 mutation receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given PO

Patients with GNAQ or GNA11 mutation receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

Other Name: Cytologic Sampling

Undergo molecular analysis

Given PO

Patients with SMO or PTCH1 mutation receive vismodegib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Optional correlative studies

The rest is here:
NCI-MATCH: Targeted Therapy Directed by Genetic Testing in ...

Genetic counseling is the process by which the patients or relatives at risk of an inherited disorder are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning. This complex process can be separated into diagnostic (the actual estimation of risk) and supportive aspects.[1]

The National Society of Genetic Counselors (NSGC) officially defines genetic counseling as the understanding and adaptation to the medical, psychological and familial implications of genetic contributions to disease.[2] This process integrates:

A genetic counselor is an expert with a Master of Science degree in genetic counseling. In the United States they are certified by the American Board of Genetic Counseling.[1] In Canada, genetic counselors are certified by the Canadian Association of Genetic Counsellors. Most enter the field from a variety of disciplines, including biology, genetics, nursing, psychology, public health and social work.[citation needed] Genetic counselors should be expert educators, skilled in translating the complex language of genomic medicine into terms that are easy to understand. Genetic counselling helps one to know the chances of inheritance of a genetic disorder so that people can make informed decisions.

Genetic counselors work as members of a health care team and act as patient advocates as well as genetic resources to physicians. Genetic counselors provide information and support to families who have members with birth defects or genetic disorders, and to families who may be at risk for a variety of inherited conditions. They identify families at risk, investigate the problems present in the family, interpret information about the disorder, analyze inheritance patterns and risks of recurrence, and review available genetic testing options with the family.

Genetic counselors are present at high risk or specialty prenatal clinics that offer prenatal diagnosis, pediatric care centers, and adult genetic centers. Genetic counseling can occur before conception (i.e. when one or two of the parents are carriers of a certain trait) through to adulthood (for adult onset genetic conditions, such as Huntington's disease or hereditary cancer syndromes).

Only some states issue licensure to genetic counselors. These states are California, Connecticut, Delaware, Idaho, Illinois, Indiana, Massachusetts, Nebraska, New Hampshire, New Jersey, New Mexico, North Dakota, Ohio, Oklahoma, Pennsylvania, South Dakota, Tennessee, Utah, and Washington. States with bills passed/in rulemaking are Hawaii, Minnesota, and Virginia.[3]

Graduates from an ABGC (American Board of Genetic Counseling) accredited program who have met specific criteria are eligible to take the examination which is offered twice per year by the ABGC. Although not every company requires its counselors to possess a certification, the certification shows that the practitioner has met the standards "necessary to provide competent genetic counseling services".[4]

Although genetic counseling has existed for over four decades, the first licenses for genetic counselors were not issues until 2002. Utah was the first state to do so. The American Society of Human Genetics (ASHG) has since encouraged more states to license genetic counselors before they are allowed to practice. The ASHG argues that requiring practitioners to go through the necessary training and testing to obtain a license will ensure quality genetic services as well as allow for reimbursement for counselors services. Laws requiring licensure ensure that "professionals who call themselves genetic counselors are able to properly explain complicated test results that could confuse patients and families making important health decisions".[5]

Insurance companies usually do not reimburse for unlicensed genetic counselors services. Patients who may benefit from genetic counseling may not be able to afford the service due to the expensive out-of-pocket cost. In addition, licensure allows genetic counselors to be searchable in most insurance companies databases which gives genetic counselors increased opportunities for earning revenue and clients the opportunity to see "the level of coverage insurers provide for their services".[5]

Any person may seek out genetic counseling for a condition they may have inherited from their biological parents.

A woman, if pregnant, may be referred for genetic counseling if a risk is discovered through prenatal testing (screening or diagnosis). Some clients are notified of having a higher individual risk for chromosomal abnormalities or birth defects. Testing enables women and couples to make a decision as to whether or not to continue with their pregnancy, and helps provide information that can be used to prepare for the birth of a child with medical issues.

A person may also undergo genetic counseling after the birth of a child with a genetic condition. In these instances, the genetic counselor explains the condition to the patient along with recurrence risks in future children. In all cases of a positive family history for a condition, the genetic counselor can evaluate risks, recurrence and explain the condition itself.

The goals of genetic counseling are to increase understanding of genetic diseases, discuss disease management options, and explain the risks and benefits of testing.[6] Counseling sessions focus on giving vital, unbiased information and non-directive assistance in the patient's decision-making process. Seymour Kessler, in 1979, first categorized sessions in five phases: an intake phase, an initial contact phase, the encounter phase, the summary phase, and a follow-up phase.[7] The intake and follow-up phases occur outside of the actual counseling session. The initial contact phase is when the counselor and families meet and build rapport. The encounter phase includes dialogue between the counselor and the client about the nature of screening and diagnostic tests. The summary phase provides all the options and decisions available for the next step. If counselees wish to go ahead with testing, an appointment is organized and the genetic counselor acts as the person to communicate the results.

Families or individuals may choose to attend counseling or undergo prenatal testing for a number of reasons.[8]

Many disorders cannot occur unless both the mother and father pass on their genes, such as cystic fibrosis; this is known as autosomal recessive inheritance. Other autosomal dominant diseases can be inherited from one parent, such as Huntington disease and DiGeorge syndrome. Yet other genetic disorders are caused by an error or mutation occurring during the cell division process (e.g. aneuploidy) and are not hereditary. Testing can reveal conditions that, while debilitating without treatment, are mild or asymptomatic with early treatment (such as phenylketonuria). Genetic tests are available for a number of genetic conditions, including but not limited to:

Patients may be referred to a genetic counselor based on the diagnosis, or a strong family history of cancer. It is estimated that only 5-10% of cancers are hereditary, meaning that these cancers are due to a gene mutation that has been passed down in the family.[9] Some examples of known cancer syndromes are hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer and Li-Fraumeni syndrome.[10] Meeting with a genetic counselor before undergoing genetic testing will help an individual to understand the test and what the results may mean for themselves and their family. Once the results are received, genetic counselors can help the patient to understand a positive or negative result. This counseling may involve providing emotional support, discussing recommendations for preventative care, screening recommendations or referrals to support groups or other resources.[11] For patients who have already been diagnosed with cancer, a positive test result may influence how the cancer is treated.[11]

Genetic Alliance states that counselors provide supportive counseling to families, serve as patient advocates and refer individuals and families to community or state support services. They serve as educators and resource people for other health care professionals and for the general public. Many engage in research activities related to the field of medical genetics and genetic counseling. The field of genetic counseling is rapidly expanding and many counselors are taking on "non-traditional roles" which includes working for genetic companies and laboratories.[citation needed] When communicating increased risk, counselors anticipate the likely distress and prepare patients for the results. Counselors help clients cope with and adapt to the emotional, psychological, medical, social, and economic consequences of the test results.

Each individual considers their family needs, social setting, cultural background, and religious beliefs when interpreting their risk.[12] Clients must evaluate their reasoning to continue with testing at all. Counselors are present to put all the possibilities in perspective and encourage clients to take time to think about their decision. When a risk is found, counselors frequently reassure parents that they were not responsible for the result. An informed choice without pressure or coercion is made when all relevant information has been given and understood.

If an initial noninvasive screening test reveals a risk to the baby, clients are encouraged to attend genetic counseling to learn about their options. Further prenatal investigation is beneficial and provides helpful details regarding the status of the fetus, contributing to the decision-making process. Decisions made by clients are affected by factors including timing, accuracy of information provided by tests, and risk and benefits of the tests. Counselors present a summary of all the options available. Clients may accept the risk and have no future testing, proceed to diagnostic testing, or take further screening tests to refine the risk. Invasive diagnostic tests possess a small risk of miscarriage (1-2%) but provide more definitive results. While families seek direction and suggestions from the counselors, they are reassured that no right or wrong answer exists. When discussing possible choices, counselor discourse predominates and is characterized by examples of what some people might do. Discussion enables people to place the information and circumstances into the context of their own lives.[13] Clients are given a decision-making framework they can use to situate themselves. Counselors focus on the importance of individual choice based on the experiences, morals, and viewpoints of the couple/individual/family. Testing is offered to provide a definitive answer regarding the presence of a certain genetic condition or chromosomal abnormality. There is often no therapy or treatment available for these conditions, and as such parents may choose to terminate the pregnancy.

After attending prenatal counseling, women have the option of accepting the risk revealed and having no further investigations during their pregnancy. They may choose to undergo noninvasive screening (e.g. ultrasound, triple screen, cell-free fetal DNA screening) or invasive diagnostic testing (amniocentesis or chorionic villus sampling).

After counseling for other hereditary conditions, the patient may be presented with the option of having genetic testing. In some circumstances no genetic testing is indicated, other times it may be useful to begin the testing process with an affected family member. The genetic counselor also reviews the advantages and disadvantages of genetic testing with the patient.

The plethora of information available can be overwhelming and counselors spend a large proportion of time clarifying details. Prenatal screening was first introduced nearly four decades ago, yet gaps still exist in public knowledge about the screening program. The general public is familiar with Down syndrome (trisomy 21), but is not aware of more uncommon conditions such as trisomy 18 (historically known as Edwards syndrome) and trisomy 13 (Patau syndrome). Clients are usually aware of diagnostic testing from friends, TV/press, or because of family history.

No simple correlation has been found between the change in technology to the changes in values and beliefs towards genetic testing.[14]

In China, genetic counseling is steered by the Chinese Board of Genetic Counseling (CBGC),[15] a not-for-profit organization. CBGC is composed of senior experts engaged in the genetics teaching and scientific researches. CBGC is committed to establishing standardized procedures of genetic counseling, training qualified genetic counselors, improving health for all, and reducing birth defects.

"Whether the process of genetic counseling is a form of psychotherapy is up for debate". The relationship between the client and counselor is similar as are the goals of the sessions. As a psychotherapist aims to help his client improve his wellbeing, a genetic counselor also helps his client to address a "situational health threat that similarly threatens client wellbeing". Due to the lack of studies which compare genetic counseling to the practice of psychotherapy, it is hard to say with certainty whether genetic counseling can be "conceptualized as a short-term, applied, specific type of psychotherapy". However, there few existing studies suggest that genetic counseling falls "significantly short of psychotherapeutic counseling" because genetic counseling sessions primarily consist of the distribution of information without much emphasis placed on explaining any long-term impacts to the client.[16]

Psychiatric genetic counseling is a controversial topic among many in the medical community. Some question its legitimacy due to the unknown cause of many psychiatric disorders. While many disorders have shown to have a genetic basis in twin studies, such knowledge means little for psychiatric genetic counseling if the exact genetic mechanism is still unknown. Those who support psychiatric genetic counseling argue that doctors can now do much more than offer risk estimates. Psychiatric genetic counselors can help "dispel mistaken notions about psychiatrist disorders, calm needless anxiety, and help those at risk to draw up a rational plan of action based on the best available information".[17]

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Genetic counseling - Wikipedia

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Aetna considers genetic testing medically necessary to establish a molecular diagnosis of an inheritable disease when all of the following are met:

The member displays clinical features, or is at direct risk of inheriting the mutation in question (pre-symptomatic); and

The result of the test will directly impact the treatment being delivered to the member; and

Achondroplasia (FGFR3)AlbinismAlpha-1 antitrypsin deficiency (SERPINA1)Alpha thalassemia/Hb Bart hydrops fetalis syndrome/HbH disease** (HBA1/HBA2, alpha globin 1 and alpha globulin 2)Angelman syndrome (GABRA, SNRPNBardet-Biedl syndromeBeta thalassemia** (beta globin)Bloom syndrome (BLM)CADASIL (see below)Canavan disease (ASPA (aspartoacylase A))Charcot-Marie Tooth disease (PMP-22)Classical lissencephalyCongenital adrenal hyperplasia/21 hydroxylase deficiency (CYP21A2)*Congenital amegakaryocytic thrombocytopeniaCongenital central hypoventilation syndrome (PHOX2B)Congenital muscular dystrophytype 1C (MDC1C) (FKRP (Fukutin related protein))Crouzon syndrome (FGFR2, FGFR3)Cystic fibrosis (CFTR) (see below)Dentatorubral-pallidoluysian atrophyDuchenne/Becker muscular dystrophy (dystrophin)Dysferlin myopathyEhlers-Danlos syndromeEmery-Dreifuss muscular dystrophy (EDMD1, 2, and 3)Fabry diseaseFactor V Leiden mutation (F5 (Factor V))Factor XIII deficiency, congenital (F13 (Factor XIII beta globulin))Familial adenomatous polyposis coli (APC) (see below)Familial dysautonomia (IKBKAP)Familial hypocalciuric hypercalcemia (see below)Familial Mediterranean fever (MEFV)Fanconi anemia (FANCC, FANCD)Fragile X syndrome, FRAXA (FMR1) (see below)Friedreich's ataxia (FRDA (frataxin))Galactosemia (GALT)Gaucher disease (GBA (acid beta glucosidase))Gitelman's syndromeHemoglobin E thalassemia **Hemoglobin S and/or C **Hemophilia A/VWF (F8 ( Factor VIII))Hemophilia B (F9 (Factor IX))Hereditary amyloidosis (TTR variants)Hereditary deafness (GJB2 (Connexin-26, Connexin-32 ))Hereditary hemorrhagic telangiectasia (HHT)Hereditary hemochromatosis (HFE) (see below)Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome (fumarate hydratase (FH) gene)Hereditary neuropathy with liability to pressure palsies (HNPP)Hereditary non-polyposis colorectal cancer (HNPCC) (MLH1, MSH2, MSH6. MSI) ( see below)Hereditary pancreatitis (PRSS1) (see below)Hereditary paraganglioma (SDHD, SDHB)

Hereditary polyposis coli (APC)Hereditary spastic paraplegia 3 (SPG3A) and 4 (SPG4, SPAST) Huntington's disease (HTT, HD(Huntington))Hypochondroplasia (FGFR3)Hypertrophic cardiomyopathy (see below)Jackson-Weiss syndrome (FGFR2)Joubert syndromeKallmann syndrome (FGFR1)Kennedy disease (SBMA)Leber hereditary optic neuropathy (LHON)Leigh Syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) Long QT syndrome (see below)Limb girdle muscular dystrophy (LGMD1, LGMD2) (FKRP (Fukutin related protein))Malignant hyperthermia (RYR1)Maple syrup urine disease (branched-chain keto acid dehydrogenase E1)Marfans syndrome (TGFBR1, TGFBR2)McArdle's diseaseMedium chain acyl coA dehydrogenase deficiency (ACADM)Medullary thyroid carcinomaMELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) (MTTL1, tRNAleu)Meckel-Gruber syndromeMucolipidosis type IV (MCOLN1, mucolipin 1)Mucopolysaccharidoses type 1 (MPS-1)Muenke syndrome (FGFR3)Multiple endocrine neoplasia type 1Muscle-Eye-Brain disease (POMGNT1)MYH-associated polyposis (MYH) (see below)Myoclonic epilepsy (MERRF) (MTTK (tRNAlys))Myotonic dystrophy (DMPK, ZNF-9)Neimann-Pick disease, type A(SMPD1, sphingomyelin phosphodiesterase)Nephrotic syndrome, congenital (NPHS1, NPHS2)Neurofibromatosis type 1 (NF1, neurofibromin)Neurofibromatosis type 2 (Merlin)Neutropenia, congenital cyclicNephronophthisisPhenylketonuria (PAH)Pfeiffer syndrome (FGFR1)Prader-Willi-Angelman syndrome (SNRPN, GABRA5, NIPA1, UBE3A, ANCR, GABRA )Primary dystonia (TOR1A (DYT1))Prothrombin (F2 (Factor II,20210G> A mutation))Pyruvate kinase deficiency (PKD)Retinoblastoma (Rh)Rett syndrome (FOXG1, MECP2)Saethre-Chotzen syndrome (TWIST, FGFR2)SHOX-related short stature (see below)Smith-Lemli-Opitz syndromeSpinal muscular atrophy (SMN1, SMN2)Spinocerebellar ataxia (SCA types 1, 2, 3 (MJD), 6 (CACNA1A), 7, 8, 10, 17 and DRPLA)Tay-Sachs disease (HEXA (hexosaminidase A))Thanatophoric dysplasia (FGFR3)Von Gierke disease (G6PC, Glycogen storage disease, Type 1a)Von Hippel-Lindau syndrome (VHL)Walker-Warburg syndrome (POMGNT1)22q11 deletion syndromes (DCGR (CATCH-22))

* Medically necessary if results of the adrenocortical profile following cosyntropin stimulation test are equivocal or for purposes of genetic counseling.

** Electrophoresis is the appropriate initial laboratory test for individuals judged to be at-risk for a hemoglobin disorder.

In the absence of specific information regarding advances in the knowledge of mutation characteristics for a particular disorder, the current literature indicates that genetic tests for inherited disease need only be conducted once per lifetime of the member.

Note: Genetic testing of Aetna members is excluded from coverage under Aetna's benefit plans if the testing is performed primarily for the medical management of other family members who are not covered under an Aetna benefit plan. In these circumstances, the insurance carrier for the family members who are not covered by Aetna should be contacted regarding coverage of genetic testing. Occasionally, genetic testing of tissue samples from other family members who are not covered by Aetna may be required to provide the medical information necessary for the proper medical care of an Aetna member. Aetna covers genetic testing for heritable disorders in non-Aetna members when all of the following conditions are met:

*** Aetna may also request a copy of the certificate of coverage from the non-member's health insurance plan if: (i) the denial letter from the non-member's insurance carrier fails to specify the basis for non-coverage; (ii) the denial is based on a specific plan exclusion; or (iii) the genetic test is denied by the non-member's insurance carrier as not medically necessary and the medical information provided to Aetna does not make clear why testing would not be of significant medical benefit to the non-member.

Medical Necessity Criteria for Specific Genetic Tests:

Adenosis polyposis coli (APC):

Aetna considers adenosis polyposis coli (APC) genetic testing medically necessary for either of the following indications:

Aetna considers APC genetic testing experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

CADASIL:

Aetna considers DNA testing for CADASIL medically necessary for either of the following indications:

Aetna considers CADASIL genetic testing experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Catecholaminergic polymorphic ventricular tachycardia (CPVT):

Aetna considers genetic testing for CPVT medically necessary for the following indications:

Cystic fibrosis:

Aetna considers genetic carrier testing for cystic fibrosis medically necessary for members in any of the following groups:

Aetna considers genetic carrier testing for cystic fibrosis experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Aetna considers a core panel of 25 mutations that are recommended by the American College of Medical Genetics (ACMG) medically necessary for cystic fibrosis genetic testing. The standard CF transmembrane regulator (CFTR)mutation panel is as follows (Available at: http://www.acmg.net

Factor V Leiden:

Aetna considers Factor V Leiden genetic testing medically necessary for members with an abnormal activated protein C (APC) resistance assay resultand any of the following indications:

Asymptomatic female who is planning pregnancy or is currently pregnant and not taking anticoagulation therapy and eitherof the following:

Aetna considers Factor V Leiden genetic testing experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Aetna considers Factor V HR2 allele DNA mutation analysis experimental and investigational because its effectiveness has not been established.

Prothrombin G20210A Thrombophilia (F2 Gene)

Aetna considers F2 gene testing for prothrombin G20210A thrombophilia when the following criteria are met:

Aetna considers F2 gene testing experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Familial nephrotic syndrome (NPHS1, NPHS2):

Aetna considers genetic testing for familial nephrotic syndrome experimental and investigational for all other indications.

Fragile X:

Aetna considers genetic testingof theFMR1 genemedically necessary for members in any of the following risk categories where the results of the test will affect a member's clinical management or reproductive decisions:

Fetuses of known carrier mothers. Prenatal testing of a fetus by amniocentesis or chorionic villus sampling is indicated following a positive Fragile X carrier test in the mother.

*POI is defined as female younger than 40 years of age with FSH levels in the postmenopausal range and at least three months of amenorrhea, oligomenorrhea or dysfunctional uterine bleeding.

Aetna considers Fragile X DNA testing medically necessary for members with a negative cytogenetic test for fragile X if they have any physical or behavioral characteristics of fragile X syndrome and have a family history of fragile X syndrome or undiagnosed developmental delay/intellectually disability.

Aetna considersFragile X DNA testing medically necessary for members with a phenotype that is not typical for fragile X syndrome who have a cytogenetic test that is positive for fragile X.

Aetna considers population-based fragile X syndrome screening of individuals who are not in any of the above-listed risk categories experimental and investigational because its effectiveness for indications other than the ones listed above has not been established.

Aetna considers genetic testing for hemoglobinopathies and thalassemias (includes, but not limited to: Sickle Cell Anemia [HBB Gene], Alpha Thalassemia [HBA1/HBA2 Genes] and Beta Thalassemia [HBB Gene]) for couples planning pregnancy or seeking prenatal care when the following criteria are met:

Hereditary hemochromatosis:

Aetna considers genetic testing for HFE gene mutations medically necessary for persons who meet all of the following criteria:

Genetic testing for hereditary hemochromatosis is considered experimental and investigational for general population screening and for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (LS):

Aetna considers genetic testing for HNPCC (MLH1, MSH2, MSH6, PMS2, EPCAMsequence analysis) medically necessary for members who meetany one of the following criteria:

Aetna considers microsatellite instability (MSI) testing or immunohistochemical (IHC) analysis of tumors medically necessary as an initial test in persons with colorectal or endometrial cancerin order to identify those persons who should proceed with HNPCC mutation analysis.

See alsoCPB 0516 - Colorectal Cancer Screening.

Hereditary pancreatitis (PRSS1):

Aetna considers genetic testing for hereditary pancreatitis (PRSS1 mutation) medically necessary in symptomatic persons with any of the following indications:

This policy is based upon guidelines from the Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, the Midwest Multi-Center Pancreatic Study Group and the International Association of Pancreatology (Ellis et al, 2001).

Aetna considers genetic testing for hereditary pancreatitis experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Long QT syndrome:

Aetna considers genetic testing for long QT syndrome medically necessary for either of the following:

Aetna considers a cardiac ion channelopathy genomic sequencing panel and duplication/deletion gene analysis panel medically necessary alternative to single gene testing.Aetna considers genetic testing for long QT syndrome experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Malignant Hyperthermia Susceptibility:

Aetna considers genetic testingfor malignant hyperthermia susceptibility (MHS) medically necessary for either of the following indications:

Aetna considersgenetic testing for malignant hyperthermia susceptibility (MHS) experimental and investigationalfor all other indications.

Aetna considersgenetic testing for central core disease (CCD)experimental and investigationalbecause there is inadequate evidence in the peer-reviewed published literature regarding its effectiveness.

MUTYH-associated polyposis:

Aetna considers testing for MUTYH mutations medically necessary for the following indications:

A clinical diagnosis of SPS is considered in an individual who meets at least one of the following empiric criteria:

Aetna considers MUTYH mutations testing experimental and investigational for any other indications because its effectiveness for indications other than the ones listed above has not been established.

Primary dystonia (DYT1):

Aetna considers genetic testing for DYT1 medically necessary for the following indications:

Aetna considers DYT-1 testing experimental and investigational for all other indications, including the following because its effectiveness for indications other than the ones listed above has not been established:

This policy is adapted from guidelines from the European Federation of Neurological Societies.

Spinal Muscular Atrophy

Aetna considers genetic testing for SMN1 and SMN2medically necessary for the following indications:

*Note: SMA includes arthrogryposis multiplex congenita-SMA (AMC-SMA), congenital axonal neuropathy (CAN), SMA0, SMA I (Werdnig-Hoffmann disease), SMA II, SMA III (Kugelberg-Welander disease) and SMA IV.

Aetna considersgenetic testing for spinal muscular atrophy (SMA)experimental and investigational for the identification of SMN1 deletion carriers in the general population and for all other indications because there is inadequate evidence in the published peer-reviewed clinical literature regarding its effectiveness.

SHOX-related short stature:

Aetna considers genetic testing for SHOX-related short stature medically necessary for children and adolescents with any of the following features:

Aetna considers genetic testing for SHOX-related short stature experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Hypertrophic cardiomyopathy (HCM):

Aetna considers genetic testing for HCM medically necessary for individuals who meet the following criteria:

Individual to be tested has been evaluated (eg, electrocardiogram [ECG], echocardiography) and exhibits no clinical evidence of HCM; and

Individual has a 1st degree relative (i.e., parent, full-sibling, child)with a known pathogenic gene mutation. (Note: Test for known familial mutation.). Aetna considers genetic testing for HCM experimental and investigational for all other indications because its effectiveness for indications other than the one listed above has not been established.

Thoracic aortic aneurysms and dissections (TAAD)

Aetna considers genetic testing for thoracic aortic aneurysms and dissections (TAAD)medically necessaryfor asymptomatic persons with an affected first-degree blood relative (i.e,. parent, full-sibling, child) with a known deleterious or suspected deleterious mutation in a gene known to cause familial TAAD. (Testing strategy: Test for known familial mutation.) Genetic testing for thoracic aortic aneurysms and dissections (TAAD) is considered experimental and investigational for any other indication, including but not limited to patients clinically diagnosed with TAAD, with a positive family history of the disorder, and for whom a genetic syndrome has been excluded.

Aetna considers TGFBR1 and TGFBR2 gene testing for LDS medically necessary when the following criteria are met:

Asymptomatic individual who has an affected first-degree blood relative (ie, parent, full-sibling, child) with a known deleterious or suspected deleterious mutation (Testing strategy: Test for known familial mutation); or

To confirm or establish a diagnosis of LDS in an individual with characteristics of LDS (eg, aortic/arterial aneurysms/tortuosity, arachnodactyly, bicuspid aortic valve and patent ductus arteriosus, blue sclerae, camptodactyly, cerebral, thoracic or abdominal arterial aneurysms and/or dissections, cleft palate/bifid uvula, club feet, craniosynostosis, easy bruising, joint hypermobility, ocular hypertelorism, pectus carinatum or pectus excavatum, scoliosis, talipes equinovarus, thin skin with atrophic scars, velvety and translucent skin, widely spaced eyes) (Testing strategy: Begin with sequence analysis of TGFBR2. If a mutation is not identified, proceed with sequence analysis of TGFBR1).

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)

Genetic testing for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is consideredmedically necessary for the following indications:

Genetic testing for ARVD/C is considered experimental and investigational for all other indications.

Osteogenesis imperfecta

Genetic testing for COL1A1 and COL1A2 gene sequencing in the management of osteogenesis imperfecta types I to IV, is consideredmedically necessary for the following indications:

Genetic testing for COL1A1 and COL1A2 gene sequencing is consideredexperimental and investigationalin any other circumstances, including, but not limited to:

Genetic testing for COL1A1/2 is considered experimental and investigational for all other indications.

Neurofibromatosis

Genetictesting for neurofibromatosis is considered medically necessary for persons who meet all of the following criteria:

Genetic testing for neurofibromatosis is considered experimental and investigational for all other indications.

Marfan syndrome

Aetna considers FNB1 gene testing forMarfan syndrome (MFS) medically necessary for the following indications:

Testing of an asymptomatic individual who has an affected first-degree blood relative (i.e,. parent, full-sibling, child) with a known deleterious or suspected deleterious mutation. (Testing strategy: Test for known familial mutation); or

Genetic testing for Marfan syndrome (MFS) is consideredexperimental and investigationalfor any other indications, including but not limited to:

Table1: Clinical Diagnostic Criteria for Marfan Syndrome

Aortic criterion (aortic diameter Z greater than or equal to two or aortic root dissection andectopia lentis*;or

Read more:
Genetic Testing - Medical Clinical Policy Bulletins | Aetna

A genetic modification therapy designed for treating pediatric leukemia has drawn both praise and caution from a Catholic bioethicist, after recently being approved by the Food and Drug Administration. While a promising use of gene modification technology, the treatment still has potentially deadly side effects - which could make the risks outweigh the benefits, says Fr. Tadeusz Pacholczyk, Ph.D., of the National Catholic Bioethics Center.

Gene therapies have garnered public attention for their potential medical significance, and because of problematic research procedures surrounding their development and the moral questions they raise. However, the new treatment, called Kymriah, is a hopeful development and a morally licit use of genetic modifications in medicine, Fr. Pacholczyk told CNA.

Because the therapy only uses matured cells from the patient, Fr. Pacholczyk explained, it does not entail the same ethical problems as other forms of gene therapy under investigation including therapies which destroy human embryos or make modifications of cells which can be passed onto future generations.

Instead, developing therapies which make genetic changes to help our immune system do better what it is supposed to do, namely identifying and eliminating various dangers from the body, is a praiseworthy goal, he said. To the extent that side effects can be limited or controlled, the therapy appears to be very promising, with reports of high success rates in slowing or even eliminating certain childhood cancers like pediatric acute lymphoblastic lymphoblastic leukemia, Fr. Pacholczyk said.

Kymriah, developed by drug company Novartis, is a highly personalized form of immunotherapy called CAR T-cell therapy. The procedure, short for Chimeric Antigen Receptor T-cell Therapy, takes a persons T-cell a kind of white blood cell and genetically modifies it to contain a new kind of protein. This protein, called a chimeric antigen receptor, or CAR, helps detect certain kinds of cancer cells. When the bodys T-cells are reintroduced to the body, they are now able to find and kill the cancer cells.

The treatment is specialized to attack a kind of pediatric cancer called acute lymphoblastic lymphoblastic leukemia, or ALL. ALL is a bone marrow and blood cancer, and is one of the most common childhood cancers in the United States. According to the FDA, over 3,000 patients under the age of 20 are diagnosed with ALL each year. The treatment will be offered to patients who have not responded to other existing treatments, or those whose cancer has returned after initial treatment.

Fr. Pacholczyk emphasized that there are some ethical concerns doctors and patients considering this treatment should investigate, particularly the potential for side effects the treatment can cause in some individuals. One ethical concern raised by this therapy centers on the question of whether the risks may be greater than the benefits for particular patients, he said.

In some patients, treatment with Kymriah can cause a severe immune response. Sometimes, when the white blood cells are rewritten, they can lead to a severe immune response called cytokine release syndrome, or CRS, when they are reintroduced. Symptoms of this syndrome can include high fever, flu symptoms, dangerously low blood pressure, and organ damage. It can also cause neurological symptoms, including swelling of the brain, which can be fatal.

In light of these dangerous side effects, the FDA also approved the expansion of use of an immune suppressing drug for treatment for CRS. The drug has shown to be an effective treatment for CRS after treatment with CAR-T cells. The FDA will also require Novartis to continue monitoring Kymriah after its release for long-term side effects and other harmful side effects.

With the control of the dangerous side effects, and weighing the risks of the treatment against its benefits, however, the new gene therapy looks promising, Fr. Pacholczyk said.

Excerpt from:
A bioethicist's take on child cancer treatment that uses gene therapy - The Tidings

For a few thousand people around the world, reaching the age of 20 is a landmark to dread, not to celebrate.

Coping since birth with Leber Congenital Amaurosis (LCA), anyone with this genetic eye disorder who hasnt already lost their sight can expect to be legally blind before they reach 21 years of age.

Characterized by deep-set eyes that are prone to involuntarily, jerky movements, LCA is caused by a fault in one or more of about 14 genes so far identified. There is no proven treatment, although that may soon change.

In late August, biotech company Spark Therapeutics Inc. ONCE, +4.60% was granted a priority review of a treatment for LCA that may make it the first gene therapy approved for use in the U.S. by the Food and Drug Administration (FDA).

Read: Novartis CAR-T therapy was the first to be approved in the U.S.

The Philadelphia-based company will by Jan. 12 discover whether the FDA will issue a biologics license for Luxturna, which can replace the faulty RPE65 gene that causes LCA with a properly functioning copy. Should it be approved, victims of this disease will soon be able to receive a single injection that may permanently restore functional eyesight.

Gene therapys payoffs

While traditional research is usually focused on unlocking a way to treat one condition, gene therapies such as Luxturna may be game changers because they are based on platforms that can be adapted and used to tackle multiple inherited disorders.

Using similar techniques, Spark is also working on a functional cure for hemophilia, a disease that afflicts about 20,000 people in the U.S. and around 400,000 globally for which the market is worth about $8.5 billion in the U.S. and European Union.

In-human trials of SPK-8011 recently showed that Sparks therapy has the potential to lift the Factor VIII protein necessary for normal blood clotting to functional and sustained levels. In short, as with the Luxturna, the therapy has the potential to offer a one-shot cure.

That would be seismic for hemophiliacs, whose main option today is regular infusions of Factor VIII protein. Unfortunately, within a few days almost none of the protein remains in the body and the hemophiliacs blood is again unable to clot normally. Spark is also developing a treatment for hemophilia B, a much smaller market.

A new dawn

Biotech companies have reached this point because research has advanced to the stage where weve figured out how to identify the genetic causes of disease and how to apply that knowledge to develop therapies that will replace defective genes to provide a lasting cure.

Voyager Therapeutics Inc. VYGR, +3.45% is focused on gene therapies for neurological disorders such as Parkinsons, Huntingtons, Lou Gehrigs disease or ALS, Friedreichs ataxia (which damages the nervous system), Alzheimers and chronic pain.

In addition to cancer immunotherapy and the more controversial gene editing, bluebird bio Inc. BLUE, +1.32% has eight gene therapy programs, including research into adrenoleukodystrophy, or ALD, a deadly brain disorder that mostly affects boys and men; beta thalassemia; and sickle cell, none of which have a cure.

Should Spark, or another company such as BioMarin Pharmaceutical Inc. BMRN, +0.67% or Sangamo Therapeutics Inc. SGMO, +5.98% which are also working on hemophilia, succeed with its gene therapy, it could adversely impact suppliers of traditional Factor VIII protein infusions, such as Shire PLC SHP, +1.39% which had revenue from hemophilia treatments of $870.9 million in the first quarter of 2017.

Cost problems

Cost has been a headwind for the two gene therapies so far approved. In April, Fierce Pharma reported that uniQure NV QURE, +2.61% would not ask the European Medicines Agency to renew its marketing authorization for Glybera, the worlds most expensive drug at $1 million, when it expires in October, because in the four years after it gained approval in 2012 it was used commercially and paid for once, according to the MIT Technology Review.

Europes other approved gene therapy has fared no better. GlaxoSmithKline Plc GSK, +0.57% said in July it is seeking a buyer for Strimvelis, a treatment for a rare inherited immune deficiency, which took a year after approval to gain its first patient.

Perhaps the solution is a new payments system for ultra-expensive and long-lasting gene therapies, based on annuities for each additional time period of a treatments effectiveness.

But how do you measure cost? In December, Biogen Inc. BIIB, +1.88% gained FDA approval for Spinraza, a treatment for spinal muscular atrophy, the leading genetic cause of infant death in the U.S. Spinraza is priced at $375,000 a year for life (after $750,000 in the first year of therapy), while a one-shot gene therapy being developed by AveXis Inc. AVXS, +0.39% for SMA may provide a cure to someone who could go on to live 80 or more years. What sort of a premium for AveXis approach is justified?

Pricing is not dissuading biotech companies. There are about 7,000 genetic diseases, and the whole pharmaceutical and biotech industry is now working to solve each of those problems.

Investors seeking to benefit from a potential medical moonshot should consider allocating capital on a long-term basis to well-managed gene therapy companies with transformative assets that give them a competitive advantage.

Ethan Lovell is co-portfolio manager of the Janus Henderson Investors Global Life Sciences strategy.

Continue reading here:
Opinion: How investors should play gene-therapy stocks - MarketWatch

In 1990, geneticist William French Anderson injectedcells with altered genes into a four-year-old girl with severe immunodeficiency disorder. This was the first sanctioned test of gene therapy, in which genetic material is used to treat or prevent disease.

If were lucky, Anderson told The Chicago Tribune, with this little girl weve opened the door for genetic engineering to attack major killers and cripplers, particularly AIDS, cancer and heart disease.

Gene therapy has never fulfilled these grand hopes. In the decades since Andersons experiment, thousands of clinical trials of gene therapies have been carried out. But the first gene therapy was only approved for sale in the U.S. this week. The Food and Drug Administration announced its approval of Kymriah, a gene therapy produced by Novartis for a form of childhood leukemia. A few gene therapies have previously become available in China and Europe.

An FDA press release emphasizes the historic nature of the approval. Were entering a new frontier in medical innovation with the ability to reprogram a patients own cells to attack a deadly cancer, FDA Commissioner Scott Gottlieb says.

As I have noted in previousposts (see Further Reading), the hype provoked by genetic research has always outrun the reality. Gene-therapy proponents have long predicted that it will eliminate diseases such as cystic fibrosis and early-onset breast cancer, which are traceable to a defective gene, as well as disorders with more complex genetic causes.Enthusiasts also envisioned genetically engineered "designer babies" who would grow up to be smarter than Nobel laureates and more athletic than Olympians.

Gene therapy turned out to be extremely difficult, because it can trigger unpredictable, fatal responses from the body's immune system.The National Institutes of Health warnsthat gene therapy can have very serious health risks, such as toxicity, inflammation, and cancer.

Kymriah is a case in point. The FDA press release warns that Kymriah can cause life-threatening immune reactions and neurological events, as well as serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). According to The New York Times, the FDA is requiring that hospitals and doctors be specially trained and certified to administer [Kymriah], and that they stock a certain drug needed to quell severe reactions.

Kymriah illustrates another problem with gene therapy: high cost. Novartis is charging $475,000 for Kymriah. As a recent Reuters article notes, over the past five years two gene therapies have been approved for sale in Europe, one for a rare blood disease and the other for the bubble-boy immunodeficiency disorder. The therapies cost $1 million and $700,000, respectively. So far, the companies that make the therapies have achieved a total of three sales.

As journalist Horace Freeland Judson points out in this excellent 2006 overview, The Glimmering Promise of Gene Therapy, biology and economics have conspired against gene therapy. Judsonnotes that most individual diseases caused by single-gene defectsthe kind that seem most likely to be cured by gene therapyare rare. (Sickle-cell anemia and some other hemoglobin disorders are among the few exceptions.)

Judson adds that because different diseases have different genetic mechanisms and affect different types of tissue, each presents a new set of research problems to be solved almost from scratch. As the millions burned away, it became clear that even with success, the cost per patient cured would continue to be enormous. And success had shown itself to be always glimmering and shifting just beyond reach.

The advent of CRISPR, a powerful gene-editing technique, has inspired hopes that gene therapy might finally fulfillexpectations. Researchers recently employed CRISPRin human embryos to counteract a mutation that causes heart disease. Potentially, The New York Times reported last month, the method could apply to any of more than 10,000 conditions caused by specific inherited mutations.

CRISPR has also renewed concerns about the ethics of engineering people with enhanced physical and mental traits. These concerns are grossly premature. As Science noted recently, CRISPR poses some of the same risks as other gene therapies. The methodstill has a long way to go before it can be used safely and effectively to repairnot just disruptgenes in people.And in fact questions have now been raised about the CRISPR research on embryos mentioned above.

Some day, applied genetics might live up to its hype, but that day is far from arriving.

Further Reading:

Could Olympians Be Tweaking Their Genes?

Have researchers really discovered any genes for behavior?

My Problem with Taboo Behavioral Genetics? The Research Stinks!

Hype of Feel-Good Gene Makes Me Feel Bad.

New York TimesHypes "Infidelity Gene."

Quest for Intelligence Genes Churns out More Dubious Results.

Warrior Gene Makes Me Mad.

Should Research on Race and IQ Be Banned?

Read this article:
Has the Era of Gene Therapy Finally Arrived? - Scientific American (blog)