Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial

Trédan, O.; Wang, Q.; Pissaloux, Daniel; Cassier, Philippe; Fouchardière, Arnaud de la; Fayette, Jérôme; Desseigne, Françoise; Ray‐Coquard, Isabelle; Fouchardière, Christelle De La; Frappaz, Didier; Heudel, Pierre; Bonneville-Levard, Alice; Fléchon, Aude; Sarabi, Mathieu; Guibert, Pierre; Bachelot, Thomas; Pérol, Maurice; You, Benoît; Bonnin, Nathalie; Collard, Olivier; Leyronnas, Cécile; Attignon, Valéry; Baudet, Christian; Sohier, Emilie; Villemin, Jean-Philippe; Viari, Alain; Boyault, Sandrine; Lantuéjoul, Sylvie; Paindavoine, Sandrine; Treillleux, I.; Rodriguez, C.; Agrapart, Vincent; Corset, Véronique; Garin, Gwenaëlle; Chabaud, Sylvie; Pérol, David; Blay, Jean‐Yves

doi:10.1093/annonc/mdz080

Cited by 147 publications

(164 citation statements)

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“…1 Large-scale studies demonstrated a limited usefulness of molecular profiling obtained from Formalin-Fixed and Paraffin-Embedded tumor specimen of primary tumor, relapse, or metastasis. 6 Tumor biopsies normally accomplish the sampling of only a part of the tumor and may only capture a fraction of its heterogeneity, consequently not being totally informative about the levels of genetic variability of a patient's cancer. Moreover, it is unlikely for a patient to undergo sequential biopsies of primary and metastatic lesions along tumor progression.…”

Section: Introductionmentioning

confidence: 99%

“…Among patients with distant metastatic disease, the visceral metastasis was the most common metastatic site (32.4%) followed by coexistence of both bone and visceral (19.1%) (Table 1). The median follow-up of OS for all patients was 3.2 months (range[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. At the time of survival analysis, death by tumor progression occurred in 12/68 (17.6%) patients.…”

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Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

et al. 2020

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Background Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti‐HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. Methods We assessed the status of a large panel of cancer driver genes by cell‐free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. Results The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1‐3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two‐points‐Next‐Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P = .026). Conclusions Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two‐point‐NGS analysis of cancer driver genes could be an efficacy tool for precision oncology.

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Section: Introductionmentioning

confidence: 99%

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Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

et al. 2020

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“…Bisgrove [75] Immunohistochemistry, Fluorescence in situ hybridization microarray IMPACT [76] PCR-based genomics and NGS SHIVA [64] Targeted NGS-based MOSCATO [39] Targeted NGS-based, RNA Seq MyPathway [77] Genomic testing Profiler [78] Targeted NGS-based I-PREDICT [79] Targeted NGS-based, ctDNA WINTHER [80] Targeted NGS-based, Transcriptomic A better understanding of cancer biology is needed to optimize and define context-dependent oncogenic mutations and resistance mechanisms. In this scenario, preclinical models, such as patientderived xenografts and organoids, may help elucidate potential codrivers and resistance mechanisms so that rational combinations can be designed and tested to support clinical deployment [81].…”

Section: Clinical Trial Molecular Toolsmentioning

confidence: 99%

Personalized Medicine: Recent Progress in Cancer Therapy

Gambardella

Tarazona

Cejalvo

et al. 2020

Cancers

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Translational research has revolutionized how we develop new treatments for cancer patients. The change from an organ-centric concept guiding treatment choice towards deep molecular analysis, driving a personalized approach, is one of the most important advances of modern oncology. Several tools such as next generation sequencing and RNA sequencing have greatly improved the capacity to detect predictive and prognostic molecular alterations. Detection of gene mutations, amplifications, and fusions has therefore altered the history of several diseases in both a localized and metastatic setting. This shift in perspective, in which attention is focused on the specific molecular alterations of the tumor, has opened the door to personalized treatment. This situation is reflected in the increasing number of basket trials selecting specific molecular targets. Nonetheless, some weaknesses need to be addressed. The complexity of cancer cells enriched with concomitant molecular alterations complicates identification of the driver. Moreover, tumor heterogeneity could be responsible for the lack of benefit when targeted agents are used. In light of this, there is growing interest in the role of multidisciplinary committees or molecular tumor boards to try to enhance selection. The aim of this review is to critically analyze the evolution of cancer treatment towards a precision approach, underlining some recent successes and unexpected failures.

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“…Comme le souligne un éditorial paru dans le même numéro de la revue Annals of Oncology [7], ces résultats décevants rejoignent ceux obtenus dans d'autres études portant au total sur plus de 13 000 patients : en moyenne, sur 1 000 malades dont l'ADN tumoral est séquencé, environ 400 présentent une mutation ciblable, 120 sont effectivement traités, et 8 à 30 seulement en bénéficient. L'analyse du déroulement de ces études montre, parmi les causes de ce faible rendement, l'importance du délai d'obtention des données moléculaires : près de trois mois pour l'article rapporté [5]. S'agissant de patients atteints d'un cancer avancé et évolutif, ils peuvent au bout de ce délai ne plus être en état de supporter le traitement, ou même être décédés.…”

Section: Bilan Et Perspectivesunclassified

“…On pourra ainsi adapter les traitements ciblés à la nature réelle de la tumeur (et non seulement au clone cellulaire majoritaire en son sein) et à son évolution au cours de la maladie. Mais, compte tenu des résultats décevants maintenant démontrés dans plusieurs essais successifs, on ne peut à ce stade envisager ces différentes mesures que dans le cadre d'essais et non d'une mise en pratique clinique de routine, comme le soulignent les auteurs de l'étude décrite [5] et, plus nettement encore, l'éditorial qui accompagne cette publication [7]. L'oncologie de précision dans laquelle on a placé beaucoup d'espoirs reste aujourd'hui un work in progress… ‡ 3 Dans cet article, les auteurs montrent que plusieurs médicaments en cours de développement ou d'essais cliniques inhibent des lignées cellulaires dans lesquelles le gène de leur cible supposée a été inactivé : ils n'agissent donc pas sur leur cible prévue mais via un autre mécanisme à élucider.…”

Section: Bilan Et Perspectivesunclassified

Les limites de l’ « oncologie de précision »

Jordan

2019

Med Sci (Paris)

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Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial

Cited by 147 publications

References 20 publications

Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

Personalized Medicine: Recent Progress in Cancer Therapy

Les limites de l’ « oncologie de précision »

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