The Added Value of Baseline Circulating Tumor DNA Profiling in Patients with Molecularly Hyperselected, Left-sided Metastatic Colorectal Cancer

Manca, Paolo; Corallo, Salvatore; Busico, Adele; Corti, Francesca; Antoniotti, Carlotta; Procaccio, Letizia; Clavarezza, Matteo; Smiroldo, Valeria; Tomasello, Gianluca; Murialdo, Roberto; Sartore‐Bianchi, Andrea; Racca, Patrizia; Pagani, Filippo; Randon, Giovanni; Martinetti, Antonia; Sottotetti, Elisa; Palermo, Federica; Perrone, Federica; Tamborini, Elena; Prisciandaro, Michele; Raimondi, Alessandra; Bartolomeo, Maria Di; Morano, Federica; Pietrantonio, Filippo

doi:10.1158/1078-0432.ccr-20-4699

Cited by 15 publications

(11 citation statements)

References 26 publications

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“…It is tempting to speculate that patients with SD disease compared to responding tumors derive the greatest benefit from post-induction treatments concepts according to FOUS4-N and PANAMA data. Biologically, tumors with PR and CR after 4-6 months of induction almost always experienced a maximal tumor response; presumably by eradicating the EGFR-sensible clonal population ( 82 , 108 , 109 ). Tumors with SD might already confer partial resistance mechanism requiring prolonged treatment or new concepts in the future ( 83 ).…”

Section: Maintenancementioning

confidence: 99%

“…Application of extended NGS based panels that cover multiple variants of secondary resistance such as MET/HER2 amplification and PIK3CA mutation could further enrich responses of re-challenge strategies (hyper- or ultraselection), although a minimal clone size value in % VAF determining resistance is still missing. For RAS mutation a cut-off of 5% was reported as a gross orientation; interestingly also small RA-MT subclones might affect response parameters depicting a significant linear correlation clone size and response to EGFR blockade ( 108 ).…”

Section: Liquid Biopsymentioning

confidence: 99%

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Current concepts of anti-EGFR targeting in metastatic colorectal cancer

Doleschal¹,

Petzer²,

Rumpold³

2022

Front. Oncol.

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Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.

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Section: Maintenancementioning

confidence: 99%

Section: Liquid Biopsymentioning

confidence: 99%

Current concepts of anti-EGFR targeting in metastatic colorectal cancer

Doleschal¹,

Petzer²,

Rumpold³

2022

Front. Oncol.

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“…Ein vielversprechender Einsatz der "liquid biopsy" ist die Detektion erworbener Resistenzen unter EGFR-Blockade [90]. Mittels ctDNA-Analytik kann die Dynamik der klonalen Evolution mit größerer Präzision im Vergleich zu Tu-morrebiopsien erfasst werden [91,92].…”

Section: Therapiemonitoring Und Monitoring Der Tumorevolutionunclassified

“…Hier ist "liquid biopsy" bereits Realität! Unter Therapie können "liquid biopsies" ein nichtinvasives Werkzeug zur Therapieüberwachung sein, beispielsweise beim KRK, wo das Auftreten RASmutierter Klone im Blut mit einer erworbenen Resistenz gegenüber Anti-EGFR-Therapiestrategien verbunden zu sein scheint [90][91][92][93][94]. Das Verschwinden dieser Klone in "liquid biopsies" kann einen Wildtypzustand anzeigen und eine Reexposition von Anti-EGFR-Strategien ermöglichen [90].…”

Section: Fazitunclassified

„Liquid biopsy“ in der gastrointestinalen Onkologie: Hype oder bald Realität?

Berger

Seufferlein

2022

J. Gastroenterol. Hepatol. Erkr.

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ZusammenfassungIn den letzten 10 Jahren sind „liquid biopsies“ bei gastrointestinalen Tumorerkrankungen deutlich in den Fokus der Wissenschaft und Forschung gerückt. Bei den neuen, blutbasierten Biomarkern, die unter dem Sammelbegriff der „liquid biopsies“ zusammengefasst werden, geht es in erster Linie um die Analyse von zirkulierender Tumor-DNA („circulating tumor DNA“, ctDNA), zirkulierenden Tumorzellen („circulating tumor cells“, CTC), zirkulierenden Mikrovesikeln (sog. Exosomen) und nichtkodierenden RNA-Molekülen (microRNA, miRNA). Für die klinische Nutzbarkeit sind besonders die einfache und flächendeckende Verfügbarkeit, aber auch zeitnahes Vorliegen von Ergebnissen wichtig, um auf dem Boden molekularer Analytik von „liquid biopsies“ klinische Entscheidungen treffen zu können. Hierfür bieten sich sog. Targeted-sequencing-Ansätze für die Analytik an, bei denen die Sequenzierung einzelner, ausgewählter Gene im Fokus steht, u. a. durch Nutzung hochsensitiver digitale PCR-Technologien. Durch „liquid biopsies“ können eine Reihe relevanter Fragestellungen adressiert werden. Neben der nichtinvasiven Diagnostik, beispielsweise bei technisch für eine Punktion schwierig zugänglichen Tumoren, sind die Überwachung unter Therapie und das Erkennen einer minimalen Resterkrankung, beispielsweise nach kurativer Therapie eines Pankreas- oder kolorektalen Karzinoms, mögliche Einsatzgebiete. Der aktuelle Stand der Wissenschaft zu „liquid biopsies“ im Feld der gastrointestinalen Onkologie mit besonderem Fokus auf das Pankreas- und kolorektale Karzinom wird in dieser Übersichtsarbeit adressiert. Handelt es sich bei „liquid biopsies“ um einen vorübergehenden Hype, oder könnte deren Einsatz bald klinischer Routine werden?

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“…13 Future directions including using dynamic biomarkers, eg, circulating tumor DNA, to better delineate who benefits more from any specific systemic approach require further investigation. 14 How do these results inform or change clinical practice? Ongoing induction chemotherapy at maximum tolerated doses is not the best strategy.…”

mentioning

confidence: 99%

Treatment Holidays for Patients With Metastatic Colorectal Cancer

Kasi

2021

JCO

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Therapy for metastatic colorectal cancers is palliative in intent for most patients. In this situation, treatment typically includes sequential combinations of chemotherapies paired with a biologic, followed by drugs such as regorafenib and trifluridine-tipiracil in the salvage setting. 1 These regimens, used alongside advances in surgery and allied fields, have improved the survival of patients with metastatic colorectal cancer from a median of 6 months from diagnosis to recent clinical trials reporting upward of a median of 42 months for all-comers. 2,3

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The Added Value of Baseline Circulating Tumor DNA Profiling in Patients with Molecularly Hyperselected, Left-sided Metastatic Colorectal Cancer

Cited by 15 publications

References 26 publications

Current concepts of anti-EGFR targeting in metastatic colorectal cancer

Current concepts of anti-EGFR targeting in metastatic colorectal cancer

„Liquid biopsy“ in der gastrointestinalen Onkologie: Hype oder bald Realität?

Treatment Holidays for Patients With Metastatic Colorectal Cancer

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