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PIK3CA Related Overgrowth Spectrum - PROS

Cancer risk


PIK3CA is an oncogene, which is a gene that has the potential to 

transform a cell into a tumour cell, and PIK3CA plays an important

role in tumor progression. There is a published article where 4 out

of 122 patients diagnosed with CLOVES syndrome developed

Wilms Tumor (also known as nephroblastoma, a rare kidney cancer,

all developed by age 2). There is a need for further risk assessment

for the other diagnosis on the spectrum, but on the basis of this article

quarterly abdominal scans up till the age of 8 (when the risk reduces) has been recommended. 



AwarenessRibbon

Genetic Testing


You would usually not find the mutation in a blood sample and due to the mosaic nature genetic testing must be preformed correctly. The mutation can be confirmed by doing a Next Generation DNA sequencing (NGS), as standard sequencing is ineffective at detecting changes that only affects a small percentage of cells. Testing should be done on affected tissue taken by puncture biopsy (or collected from surgery). For patients with face/head involvement a non-invasive buccal swab, also called a cheek-swab have shown a high diagnostic sensitivity similar to detection rate in tissue biopsi. Other testing options for patients with face/head involvement are testing on shed teeth or gingival (gum) biopsy. The latter option can be done as a "brush biopsy" which is non-invasive. Since the mutation is mosaic a negative result does not necessarily rule out a clinical diagnosis on the PIK3CA Related Overgrowth Spectrum.


The significance of a confirmed mutation is espicially due of the rising

potential of pharmacological intervention.


I.e. targeted therapy/precision medicine and present and upcoming clinical trials where you’ll need a documented mutation in order to be considered for treatment.

Treatments


Management will vary greatly depending on what's affected, but there is currently no cure for PROS conditions and treatment options are few. For surgical interventions there can often be seen recurrence of the overgrowth.


The advances made in targeted therapy is creating new hope for potential treatment.


One of the most promising drug treatments currently is the PIK3CA inhibitor

Alpelisib which have shown remarkable results in a (non clinical) study.

“During 6 months of treatment, all patients showed substantial clinical

improvement”. One of the authors of the article, Dr.Canaud, held a speech

about the results at the ESHG 2019. You can watch it here (from 57:00).

A clinical trial is rumored to start within 2020 (COVID-19 delays may occur). 


The current drug treatment options are targeted therapeutic drugs in the

PI3K/AKT/mTOR signalling pathway. There are also several single, dual

and multi-target inhibitors for this pathway currently in development for

the treatment of several different forms of cancer. 


Below is a description of the drug options currently available upon eligibility.

PIK3CA-AKT-MTOR-Pathway


PIK3CA inhibitor

Generic name: Alpelisib Brand Name: Piqray / BYL719


Alpelisib was FDA approved under the brand name Piqray the summer of 2019 for the treatment of HR+/HER2- advanced breast cancer (in combination with a fulvestrant). Approved by the EC and Health Canada summer 2020.

A (non clinical) study was published in the science journal Nature in June 2018 about a cohort of 19 PROS patients who all demonstrated clinical improvements and minimal side effects by this treatment (long term side effects still unknown). This drug is currently only available through compassionate use program/managed access program, for those who are eligable. A clinical trial for PROS patients is rumored to start soon (2020 - but the pandemic may delay the startup). A retrospective study of PROS patients who have received Alpelisib as part of a compassionate use program started June 9th with estimated completion date September 29th. 



Topical gel Product name: VT30 from Venthera

First human trial of VT30 is upcoming for patients aged ≥ 18 years

with Veneous/Lymphatic Malformations with confirmed PIK3CA (or TEK) mutations. Estimated startup

September 2020. The topical gel enables enzymes to produce VT10, a potent inhibitor of PIK3CA.

Applied directly to the lesion and thus bypassing the need for systemic administration.


pan AKT-inhibitor 

Generic name: Miransertib Name: ARQ-092 / MK-7075


This drug is currently in clinical trial for the treatment of both PROS and Proteus Syndrome (another overgrowth condition caused by AKT1 mutation). Interim data from phase 1/2 of this trial showed a manageable safety profile and the majority of patients demonstrated no disease progression. This trial is still open for recruitment. A preprint of an article (not undergone peer review) published May 29th 2020 on the use of this drug in two children (one wit FIL) can be found here. Both discontinued the use of

Miransertib to start Alpelisib. 



mTOR-inhibitors

Generic name: Sirolimus Brand Name: Rapamune / Rapamycin (exists as both oral and topical)

Generic name: Everolimus Brand Name: Afinitor / Votubia / Zortress (US) / Certican (EU +) / Evertor


Sirolimus is a drug indicated for posttransplant immunosuppression, but there has been off-label(*) use of this drug for patients with overgrowth diseases for several years. The conclusion from a recent study of Rapamycin in PROS patients: “This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS.”

A related drug to Sirolimus, also an mTOR inhibitor, is everolimus, marketed under different brand names for different indications but they have the same active ingredient. Everolimus is also being used off-label for patients with overgrowth conditions.

*Off-label means the use of a drug for a condition other than for that which it has been officially approved for.

Conditions on the PIK3CA Related Overgrowth Spectrum 


Most of these conditions were defiened as single diagnostic entities before the genetic cause was known. Many patients may experience overlaps of features from the conditions on the spectrum. Following is a brief description of the currently identifyed conditions associated with the PIK3CA-Related Overgrowth Spectrum.

HME

A neurological condition where one-half of the brain is abnormally larger than the other. The structure of the brain on the affected side may be markedly abnormal or show only subtle changes. 


ILM

Isolated Lymphatic Malformation is characterized by fluid filled masses that often occur in the head and neck region.


KTS

Key features are capillary, lymphatic and venous malformations as well as bone and soft-tissue hypertrophy.


M-CM /MCAP

Megalencephaly-capillary malformation syndrome´s primary features are large brain (megalencephaly) and abnormalities of small blood vessels in the skin called capillaries (capillary malformations). Some also have segmental overgrowth.


Macrodactyly

Isolated overgrowth and malformation of a digit, whether of the hand or foot.


Muscular HemiHyperplasia

Overgrowth on one side of the body and may also be referred to as muscular hemihypertrophy 


Skin lesions - Epidermal Nevus,benign lichenoid keratosis, or seborrheic keratosis

Abnormal overgrowth of cells in the skin.

CLAPO syndrome

Key features are capillary malformation of the lower lip, lymphatic malformation mainly on the face and neck, asymmetry, and partial/generalized overgrowth


CLOVES syndrome

CLOVES is an acronym for Congenital Lipomatous Overgrowth, Vascular malformation, Epidermal nevi, Skeletal/Spinal/scoliosis. Some of the most consistent features are Fatty Truncal Mass, vascular anomalies, skin lesions and abnormal extremities.


FAVA

Fibro-Adipose Vascular Anomaly is characterized by tough, fibrous, fatty tissue infiltrating a muscle in one or more limbs. FAVA can also cause venous and/or lymphatic abnormalities.


FAO

Fibroadipose hyperplasia (FH) or Overgrowth (FAO)

Characterized by progressive patchy fatty, fibrous and/or blood vessel overgrowth of a limb or part of the body.


FIL

Facial Infiltrating Lipomatosis - A craniofacial overgrowth condition affecting one half of the face/skull. It affects both soft and hard tissues (facial skeleton including teeth).


HHML

HemiHyperplasia-Multiple Lipomatosis is a condition with key features being asymmetric nonprogressive overgrowth, multiple lipomas, and superficial vascular malformations



    Articles about PIK3CA Related Overgrowth Spectrum - PROS



    2012 - Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES Syndrome

    2012 - Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA

    2014 - Clinical delineation and natural history of the PIK3CA‐related overgrowth spectrum

    2015 - PIK3CA-Related Overgrowth Spectrum (PROS): Diagnostic and Testing Eligibility Criteria, Differential Diagnosis, and Evaluation

    2015 - Mouse models of human PIK3CA-related brain overgrowth have 1 acutely treatable epilepsy

    2015 -  Heterozygous expression of the oncogenic Pik3caH1047R mutation during murine development results in fatal embryonic and extraembryonic defects

    2015 - Sirolimus Effect on Hypertrophic Syndromes Related Gene PIK3CA

    2016 - Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans

    2016 - Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation

    2016 - PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

    2017 - Mosaic Disorders and the Taxonomy of Human Disease

    2017 - ArQule Announces First Patient Dosed in Company Sponsored Phase 1/2 Trial of AKT Inhibitor, ARQ 092, for Rare Overgrowth Diseases

    2017 - Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing

    2018 - Cancer-Associated PIK3CA Mutations in Overgrowth Disorders

    2018 - Certain skin conditions signal potential overgrowth disorder

    2018 - Understanding activating PIK3CA mutations in human disease

    2018 - PI3K/mTOR inhibition promotes the regression of experimental vascular malformations driven by PIK3CA-activating mutations

    2018 - Syndrome d "elephant man": enfin un espoir de traitement

    2018 - Targeted therapy in patients with PIK3CA-related overgrowth syndrome

    2018 - Lessons for cancer drug treatment from tackling a non-cancerous overgrowth syndrome

    2019 - Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner

    2019 - Report by Dr. R Madson from PI3K/PTEN pathway scientific meeting, July 2019

    2020 - Clinical Experience with the AKT1 Inhibitor Miransertib in two Children with PIK3CA-related overgrowth syndrome (preprint)

    2020 - Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation

    2020 - PIK3CA vascular overgrowth syndromes: an update

    2020 - Rheumatoid Arthiritis & CLOVES Syndrome: A Tricky Diagnosis

    2020 - Gingival Biopsy to Detect Mosaicism in Overgrowth Syndromes: Report of Two Cases of Megalencephaly-Capillary Malformation Syndrome with Periodontal Anomalies

    2020 - Overgrowth Syndromes and New Therapies


    PROS Related Websites

    PROS Spectrum - Novartis has created a website about PROS geared towards physicians

    Other PROS conditions patient organizations

    See mouseover text for a brief description of each organization.

    Italian Macrodactyly and PROS organization
    French organization for CLOVES syndrome
    US based organization for CLOVES Syndrome
    M-CM Spain
    US based organization for CLOVES Syndrome
    US based Klippel-Trenaunay Support Group
    UK based organization - Genetic Overgrowth PI3K Support
    US based - M-CM Network
    M-CM UK

    This website is intended to connect families and people with Facial Infiltrating Lipomatosis (FIL), share experiences, provide information and support.

    It is not intended for medical diagnostic use or to replace medical consultation. No images on this website may be used or reproduced.  

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