Tumor Fraction Correlates With Detection of Actionable Variants Across &gt; 23,000 Circulating Tumor DNA Samples

Husain, Hatim; Pavlick, Dean C.; Fendler, Bernard J.; Madison, Russell; Decker, Brennan; Gjoerup, Ole; Parachoniak, Christine A.; McLaughlin-Drubin, Molly; Erlich, Rachel; Schrock, Alexa B.; Frampton, Garrett M.; Thakur, Meghna Das; Oxnard, Geoffrey R.; Tukachinsky, Hanna

doi:10.1200/po.22.00261

Cited by 50 publications

(30 citation statements)

References 25 publications

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“…For the SANDPIPER cohort, the clonality of each PIK3CA mut was estimated based on the alteration allele fraction and the estimated ctDNA fraction. The ctDNA fraction was estimated based on tumor aneuploidy or maximum somatic allele fraction, as described previously [ 21 – 23 ]. Briefly, when there is clear evidence of aneuploidy (~ 10% tumor shed), an aneuploidy-based estimate of tumor fraction is used.…”

Section: Methodsmentioning

confidence: 99%

Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2–, PIK3CA-mutated breast cancers

Hutchinson¹,

Chen²,

Savage³

et al. 2023

Genome Med

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Background Mutations in the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), encoded by the PIK3CA gene, cause dysregulation of the PI3K pathway in 35–40% of patients with HR+/HER2– breast cancer. Preclinically, cancer cells harboring double or multiple PIK3CA mutations (mut) elicit hyperactivation of the PI3K pathway leading to enhanced sensitivity to p110α inhibitors. Methods To understand the role of multiple PIK3CAmut in predicting response to p110α inhibition, we estimated the clonality of multiple PIK3CAmut in circulating tumor DNA (ctDNA) from patients with HR+/HER2– metastatic breast cancer enrolled to a prospectively registered clinical trial of fulvestrant ± taselisib, and analyzed the subgroups against co-altered genes, pathways, and outcomes. Results ctDNA samples with clonal multiple PIK3CAmut had fewer co-alterations in receptor tyrosine kinase (RTK) or non-PIK3CA PI3K pathway genes compared to samples with subclonal multiple PIK3CAmut indicating a strong reliance on the PI3K pathway. This was validated in an independent cohort of breast cancer tumor specimens that underwent comprehensive genomic profiling. Furthermore, patients whose ctDNA harbored clonal multiple PIK3CAmut exhibited a significantly higher response rate and longer progression-free survival vs subclonal multiple PIK3CAmut. Conclusions Our study establishes clonal multiple PIK3CAmut as an important molecular determinant of response to p110α inhibition and provides rationale for further clinical investigation of p110α inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types.

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Section: Methodsmentioning

confidence: 99%

Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2–, PIK3CA-mutated breast cancers

Hutchinson¹,

Chen²,

Savage³

et al. 2023

Genome Med

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“…These false‐negative results reflect low levels of ctDNA in some patients (with limited‐stage disease and low tumor burden), and some specific tumor types are associated with less shedding of tumor DNA into the circulation 40,41,81 . It may be possible to define a threshold, based on the absolute level of tumor DNA detected in the plasma, above which false‐negative results are unlikely to arise 89,90 . In patients with lower levels of ctDNA, a negative result cannot reliably exclude the presence of a mutation, such that repeat biopsy should be considered where analysis does not identify driver mutations.…”

Section: Reading and Interpreting An Ngs Reportmentioning

confidence: 99%

Interpreting and integrating genomic tests results in clinical cancer care: Overview and practical guidance

Casolino,

Beer,

Chakravarty

et al. 2024

CA A Cancer J Clinicians

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The last decade has seen rapid progress in the use of genomic tests, including gene panels, whole‐exome sequencing, and whole‐genome sequencing, in research and clinical cancer care. These advances have created expansive opportunities to characterize the molecular attributes of cancer, revealing a subset of cancer‐associated aberrations called driver mutations. The identification of these driver mutations can unearth vulnerabilities of cancer cells to targeted therapeutics, which has led to the development and approval of novel diagnostics and personalized interventions in various malignancies. The applications of this modern approach, often referred to as precision oncology or precision cancer medicine, are already becoming a staple in cancer care and will expand exponentially over the coming years. Although genomic tests can lead to better outcomes by informing cancer risk, prognosis, and therapeutic selection, they remain underutilized in routine cancer care. A contributing factor is a lack of understanding of their clinical utility and the difficulty of results interpretation by the broad oncology community. Practical guidelines on how to interpret and integrate genomic information in the clinical setting, addressed to clinicians without expertise in cancer genomics, are currently limited. Building upon the genomic foundations of cancer and the concept of precision oncology, the authors have developed practical guidance to aid the interpretation of genomic test results that help inform clinical decision making for patients with cancer. They also discuss the challenges that prevent the wider implementation of precision oncology.

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“…In cfDNA analysis, tumor volume can affect the detection of ctDNA, since the amount of ctDNA released in the bloodstream depends on tumor volume [22]. If the tumor volume is small, it may result in less ctDNA being released into the bloodstream, causing falsenegative results.…”

Section: Difficulty Of Detecting Copy Number Lossmentioning

confidence: 99%

The Current State and Future of Plasma Cell-Free DNA Analysis in Urologic Malignancies

Akamatsu

Mizuno

Sumiyoshi

et al. 2023

Korean J Urol Oncol

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Genomic medicine based on comprehensive genomic profiling (CGP) has revolutionized cancer treatment. However, there are certain limitations to CGP based on tissue analysis. Liquid biopsy, particularly plasma cell-free DNA (cfDNA), has emerged as a less invasive source of information to complement tissue-based analysis. To use cfDNA analysis effectively in the clinical setting, it is important to know the characteristics and specific limitations of cfDNA analysis. Moreover, the utility of cfDNA testing differs between cancer types, which is not widely recognized. Furthermore, in addition to its use in CGP, there are broader applications for cfDNA testing, including its use in detecting minimal residual disease or even epigenomic profiling. In this review, we first describe the detailed characteristics of cfDNA and the limitations of cfDNA analysis, and then focus on the utility of cfDNA analysis in urologic malignancies.

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Tumor Fraction Correlates With Detection of Actionable Variants Across > 23,000 Circulating Tumor DNA Samples

Cited by 50 publications

References 25 publications

Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2–, PIK3CA-mutated breast cancers

Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2–, PIK3CA-mutated breast cancers

Interpreting and integrating genomic tests results in clinical cancer care: Overview and practical guidance

The Current State and Future of Plasma Cell-Free DNA Analysis in Urologic Malignancies

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