Proposal for a Combined Histomolecular Algorithm to Distinguish Multiple Primary Adenocarcinomas from Intrapulmonary Metastasis in Patients with Multiple Lung Tumors

Lupo, Audrey; Barritault, Marc; Alifano, Marco; Janet-Vendroux, Aurélie; Zarmaev, Makmoud; Biton, Jérôme; Velut, Yoan; Hay, Christine Le; Cremer, Isabelle; Régnard, Jean-François; Fournel, Ludovic; Rance, Bastien; Wislez, Marie; Laurent‐Puig, Pierre; Herbst, Ronald; Damotte, Diane; Blons, Hélène

doi:10.1016/j.jtho.2019.01.017

Cited by 61 publications

(62 citation statements)

References 49 publications

(61 reference statements)

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“…The breast is a rather unique organ regarding the clonality issue between DCIS and its recurrence, although a similar issue exists in the liver and the lungs, where intra-organ metastases have to be discerned from new, metachronous and synchronous carcinomas. 100,101 Based on the currently available evidence regarding prognostic markers in DCIS (or the lack thereof), we propose a new model as a retrospective surrogate for active surveillance trials, which may provide useful data on the short term. This novel strategy is based on the comparison of the initial DCIS lesion between the patients who developed an in situ recurrence and the patients who developed an invasive recurrence.…”

Section: Resultsmentioning

confidence: 99%

A retrospective alternative for active surveillance trials for ductal carcinoma in situ of the breast

Bockstal

Agahozo

Koppert

et al. 2019

Intl Journal of Cancer

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Ductal carcinoma in situ (DCIS) of the breast is a nonobligate precursor of invasive breast cancer, accounting for 20 % of screen‐detected breast cancers. Little is known about the natural progression of DCIS because most patients undergo surgery upon diagnosis. Many DCIS patients are likely being overtreated, as it is believed that only around 50 % of DCIS will progress to invasive carcinoma. Robust prognostic markers for progression to invasive carcinoma are lacking. In the past, studies have investigated women who developed a recurrence after breast‐conserving surgery (BCS) and compared them with those who did not. However, where there is no recurrence, the patient has probably been adequately treated. The present narrative review advocates a new research strategy, wherein only those patients with a recurrence are studied. Approximately half of the recurrences are invasive cancers, and half are DCIS. So‐called “recurrences” are probably most often the result of residual disease. The new approach allows us to ask: why did some residual DCIS evolve to invasive cancers and others not? This novel strategy compares the group of patients that developed in situ recurrence with the group of patients that developed invasive recurrence after BCS. The differences between these groups could then be used to develop a robust risk stratification tool. This tool should estimate the risk of synchronous and metachronous invasive carcinoma when DCIS is diagnosed in a biopsy. Identification of DCIS patients at low risk for developing invasive carcinoma will individualize future therapy and prevent overtreatment.

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Section: Resultsmentioning

confidence: 99%

A retrospective alternative for active surveillance trials for ductal carcinoma in situ of the breast

Bockstal

Agahozo

Koppert

et al. 2019

Intl Journal of Cancer

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“…This genetic model is also supported by studies which investigated EGFR and KRAS mutations in matched primary tumor and metastasis from the same patients and reported the occasional presence of KRAS mutations in metastatic lesions from EGFR mutant primary tumors ( 27 ). Moreover, up to 8–15% NSCLC are diagnosed with multiple lung nodules and can disclose extensive inter-tumor genetic variation in the same patient ( 28 , 29 ).…”

Section: Discussionmentioning

confidence: 99%

Detection of Low-Frequency KRAS Mutations in cfDNA From EGFR-Mutated NSCLC Patients After First-Line EGFR Tyrosine Kinase Inhibitors

et al. 2021

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BackgroundMolecular profiling of advanced EGFR mutated NSCLC has recently demonstrated the co-existence of multiple genetic alterations. Specifically, co-existing KRAS-mutations in EGFR NSCLCs have been described, despite their prevalence at progression and their role in the response to EGFR tyrosine kinase inhibitors (TKIs) remain marginally explored. Aim of our study was to investigate the prevalence of co-existing KRAS mutations at the time of progressive disease and explore their impact on clinical outcome.Materials and MethodsWe retrospectively analyzed by digital droplet PCR prevalence of KRAS co-mutations in 106 plasma samples of EGFR mutated NSCLC patients, in progressive disease after EGFR TKI treatment as first-line therapy.ResultsKRAS co-mutations (codon 12 and 13) were identified in 3 patients (2.8% of analyzed samples), with low allelic frequency (<0.2%), and had a negative impact on clinical outcome to first-line EGFR TKI.ConclusionDetection of KRAS mutations in cell-free DNA of EGFR mutant NSCLC patients at progression after first or second generation EGFR TKI is a rare event. Due to their low abundance, the negative impact of KRAS mutations on the response to EGFR TKI remains to be confirmed in larger studies.

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“…These alterations could stem from EGFR-mutated tumor cells but also from tumor clones lacking EGFR mutation. Furthermore, recent studies have uncovered that in patients with multiple pulmonary nodules, which represent up to 10% of all lung cancers, a sizeable quota are independent tumors, which disclose a completely different genetic makeup [19,20].…”

Section: Discussionmentioning

confidence: 99%

Detection of Loss of Heterozygosity in cfDNA of Advanced EGFR- or KRAS-Mutated Non-Small-Cell Lung Cancer Patients

Boldrin

Nardo

Zulato

et al. 2019

IJMS

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Liquid biopsy is currently approved for management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. However, one unanswered question is whether the rate of cell-free DNA (cfDNA)-negative samples is due to technical limitations rather than to tumor genetic characteristics. Using four microsatellite markers that map specific chromosomal loci often lost in lung cancer, we conducted a pilot study to investigate whether other alterations, such as loss of heterozygosity (LOH), could be detected in EGFR-negative cfDNA. We analyzed EGFR-mutated NSCLC patients (n = 24) who were positive or negative for EGFR mutations in cfDNA and compared the results with a second cohort of 24 patients bearing KRAS-mutated cancer, which served as a representative control population not exposed to targeted therapy. The results showed that in EGFR-negative post-tyrosine-kinase-inhibitor (TKI) cfDNAs, LOH frequency was significantly higher than in both pre- and post-TKI EGFR-positive cfDNAs. By contrast, no association between KRAS status in cfDNA and number of LOH events was found. In conclusion, our study indicates the feasibility of detecting LOH events in cfDNA from advanced NSCLC and suggests LOH analysis as a new candidate molecular assay to integrate mutation-specific assays.

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Proposal for a Combined Histomolecular Algorithm to Distinguish Multiple Primary Adenocarcinomas from Intrapulmonary Metastasis in Patients with Multiple Lung Tumors

Cited by 61 publications

References 49 publications

A retrospective alternative for active surveillance trials for ductal carcinoma in situ of the breast

A retrospective alternative for active surveillance trials for ductal carcinoma in situ of the breast

Detection of Low-Frequency KRAS Mutations in cfDNA From EGFR-Mutated NSCLC Patients After First-Line EGFR Tyrosine Kinase Inhibitors

Detection of Loss of Heterozygosity in cfDNA of Advanced EGFR- or KRAS-Mutated Non-Small-Cell Lung Cancer Patients

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