Molecular diagnostics can offer important benefits to patients and are a key enabler of the integration of personalised medicine into health care systems. However, despite their promise, few molecular diagnostics are embedded into clinical practice (especially in Europe) and access to these technologies remains unequal across countries and sometimes even within individual countries. If research translation and the regulatory environments have proven to be more challenging than expected, reimbursement and value assessment remain the main barriers to providing patients with equal access to molecular diagnostics. Unclear or non-existent reimbursement pathways, together with the lack of clear evidence requirements, have led to significant delays in the assessment of molecular diagnostics technologies in certain countries. Additionally, the lack of dedicated diagnostics budgets and the siloed nature of resource allocation within certain health care systems have significantly delayed diagnostics commissioning. This article will consider the perspectives of different stakeholders (patients, health care payers, health care professionals, and manufacturers) on the provision of a research-enabled, patient-focused molecular diagnostics platform that supports optimal patient care. Through the discussion of specific case studies, and building on the experience from countries that have successfully integrated molecular diagnostics into clinical practice, this article will discuss the necessary evolutions in policy and health technology assessment to ensure that patients can have equal access to appropriate molecular diagnostics.
In: Scholl , S M , Beal , J , de Koning , L , Girard , E , Popovic , M , de la Rochefordière , A , Lecuru , F , Fourchotte , V , Ngo , C , Floquet , A , Berns , E MJJ , Kenter , G , Gestraud , P , von der Leyen , H , Lecerf , C , Puard , V , Roman , S R , Latouche , A , Kereszt , A , Balint , B , Rouzier , R & Kamal , M 2020 , ' Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer ' , EBioMedicine , vol. 61 , 103049 . https://doi.org/10.1016/j.ebiom.2020.103049
BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality world wide and constitutes the third most common malignancy in women. The RAIDs consortium (http://www.raids-fp7.eu/) conducted a prospective European study [BioRAIDs (NCT02428842)] with the objective to stratify CC patients for innovative treatments. A "metagene" of genomic markers in the PI3K pathway and epigenetic regulators had been previously associated with poor outcome [2]. METHODS: To detect new, more specific, targets for treatment of patients who resist standard chemo-radiation, a high-dimensional Cox model was applied to define dominant molecular variants, copy number variations, and reverse phase protein arrays (RPPA). FINDINGS: Survival analysis on 89 patients with all omics data available, suggested loss-of-function (LOF) or activating molecular alterations in nine genes to be candidate biomarkers for worse prognosis in patients treated by chemo-radiation while LOF of ATRX, MED13 as well as CASP8 were associated with better prognosis. When protein expression data by RPPA were factored in, the supposedly low molecular weight and nuclear form, of beta-catenin, phosphorylated in Ser552 (pβ-Cat552), ranked highest for good prognosis, while pβ-Cat675 was associated with worse prognosis. INTERPRETATION: These findings call for molecularly targeted treatments involving p53, Wnt pathway, PI3K pathway, and epigenetic regulator genes. Pβ-Cat552 and pβ-Cat675 may be useful biomarkers to predict outcome to chemo-radiation, which targets the DNA repair axis. FUNDING: European Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer.
BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality world wide and constitutes the third most common malignancy in women. The RAIDs consortium (http://www.raids-fp7.eu/) conducted a prospective European study [BioRAIDs (NCT02428842)] with the objective to stratify CC patients for innovative treatments. A "metagene" of genomic markers in the PI3K pathway and epigenetic regulators had been previously associated with poor outcome [2]. METHODS: To detect new, more specific, targets for treatment of patients who resist standard chemo-radiation, a high-dimensional Cox model was applied to define dominant molecular variants, copy number variations, and reverse phase protein arrays (RPPA). FINDINGS: Survival analysis on 89 patients with all omics data available, suggested loss-of-function (LOF) or activating molecular alterations in nine genes to be candidate biomarkers for worse prognosis in patients treated by chemo-radiation while LOF of ATRX, MED13 as well as CASP8 were associated with better prognosis. When protein expression data by RPPA were factored in, the supposedly low molecular weight and nuclear form, of beta-catenin, phosphorylated in Ser552 (pβ-Cat552), ranked highest for good prognosis, while pβ-Cat675 was associated with worse prognosis. INTERPRETATION: These findings call for molecularly targeted treatments involving p53, Wnt pathway, PI3K pathway, and epigenetic regulator genes. Pβ-Cat552 and pβ-Cat675 may be useful biomarkers to predict outcome to chemo-radiation, which targets the DNA repair axis. FUNDING: European Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer.
In: Scholl , S , Popovic , M , de la Rochefordiere , A , Girard , E , Dureau , S , Mandic , A , Koprivsek , K , Samet , N , Craina , M , Margan , M , Samuels , S , Zijlmans , H , Kenter , G , Hillemanns , P , Dema , S , Dema , A , Malenkovic , G , Djuran , B , Floquet , A , Garbay , D , Guyon , F , Colombo , P E , Fabbro , M , Kerr , C , Ngo , C , Lecuru , F , Campo , E R D , Coutant , C , Marchal , F , Mesgouez-Nebout , N , Fourchotte , V , Feron , J G , Morice , P , Deutsch , E , Wimberger , P , Classe , J-M , Gleeson , N , von der Leyen , H , Minsat , M , Dubot , C , Gestraud , P , Kereszt , A , Nagy , I , Balint , B , Berns , E , Jordanova , E , Saint-Jorre , N D , Savignoni , A , Servant , N , Hupe , P , de Koning , L , Fumoleau , P , Rouzier , R & Kamal , M 2019 , ' Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome ' , EBioMedicine , vol. 43 , pp. 253-260 . https://doi.org/10.1016/j.ebiom.2019.03.069
Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. Fund: European Union's Seventh Program grant agreement No 304810.