[18F]FDG and [18F]FES PET/CT Imaging as a Biomarker for Therapy Effect in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant

PURPOSE: Positron emission tomography (PET) with 16α-[18F]-fluoro-17β-estradiol ([18F]FES) allows assessment of whole body estrogen receptor (ER) expression. The aim of this study was to investigate [18F]fluorodeoxyglucose ([18F]FDG) and [18F]FES PET/CT imaging for response prediction and monitoring of drug activity in patients with metastatic ER+ breast cancer undergoing treatment with the selective estrogen receptor downregulator (SERD) rintodestrant.PATIENTS AND METHODS: In this trial (NCT03455270), PET/CT imaging was performed at baseline ([18F]FDG and [18F]FES), during treatment and at time of progression (only [18F]FES). Visual, quantitative and mutational analysis was performed to derive a heterogeneity score (HS) and assess tracer uptake in lesions, in relation to the mutation profile. The primary outcome was progression-free survival (PFS).RESULTS: The HS and PFS in the entire group did not correlate (n=16, Spearman's rho, P=0.06), but patients with a low HS (&lt;25.0%, n=4) had a PFS of &gt;5 months whereas patients with no [18F]FES uptake (HS 100.0%, n =3) had a PFS of &lt;2 months. [18F]FES uptake was not affected by ESR1 mutations. On-treatment [18F]FES PET/CT scans showed no [18F]FES uptake in any of the baseline [18F]FES positive lesions. At progression, [18F]FES uptake remained blocked in patients scanned ≤1-2 half-lives of rintodestrant whereas it restored in patients scanned ≥5 days after end of treatment.CONCLUSION: Absence of ER expression on [18F]FES PET is a predictor for no response to rintodestrant. [18F]FES uptake during treatment and at time of progression is useful to monitor the (reversible) effect of therapy and continued mode of action of SERDs.</p

The contribution of molecular imaging to early evaluation of response to anti-HER2 agents in Breast Cancer

L’imagerie en oncologie a fait des progrès considérables ces dernières années avec l’introduction du CT scan spiralé, de la résonance magnétique, de la mammographie digitalisée et du PET scan. Des combinaisons de différentes techniques ont vu le jour, telles que le PET/CT, et améliorent encore les possibilités de stadification de la maladie cancéreuse ainsi que le monitoring de son évolution dans le temps, et notamment sous traitement.Parallèlement, de grands progrès thérapeutiques ont étés réalisés en oncologie, en particulier le développement de médicaments « ciblés » dont l’efficacité dépend de l’expression par la cellule tumorale d’une molécule cible jouant un rôle important dans sa survie et/ou sa prolifération. L’expression de la molécule cible est une condition nécessaire mais pas suffisante pour observer une réponse au traitement ciblé :l’échec de ce dernier peut aussi s’expliquer par des altérations moléculaires en amont ou en aval de la « cible ».Le cancer du sein dit « HER2 positif » représente 20 à 25% des cancers du sein. Celui-ci est caractérisé par l’expression membranaire, en quantités importantes, d’une protéine, appelée HER2, qui lui confère une biologie agressive et un mauvais pronostic. L’expression de HER2 au niveau de la tumeur, déterminée en routine clinique par immunohistochimie et/ou par hybridation in situ en fluorescence, est le seul biomarqueur validé aujourd’hui dans le cancer du sein HER2 positif pour prédire l’efficacité des traitements ciblés anti-HER2. Cette prédiction est toutefois peu satisfaisante en termes de valeur prédictive positive (50% environ). Après une revue de la litérature sur les études d’imagerie fonctionnelle, peu nombreuses, réalisées dans le cancer du sein HER2 positif, nous avons décidé d’explorer le rôle de l’imagerie moléculaire avec la technologie PET/CT dans l’individualisation de la prise en charge du cancer du sein HER2 positif avec deux radio traceurs (FDG et zirconium89-trastuzumab), et ce, dans deux contextes cliniques distincts :dans la maladie précoce soumise à un traitement neoadjuvant et dans le contexte métastatique, en cas de traitement par le T-DM1.Doctorat en Sciences médicales (Médecine)info:eu-repo/semantics/nonPublishe

New PET imaging agents in the management of solid cancers.

(18)F-fluoro-2-deoxy-D-glucose PET-computed tomography (CT) has a major clinical impact in oncology not only for diagnostics but also for staging, response assessment, and relapse detection. However, several other PET tracers are needed for a more complete molecular characterization of cancers which has great importance in the era of individualized targeted therapies. PET-CT is an exquisite tool for molecular imaging because it allows detection of nanomolar quantities of tracer molecules targeting different hallmarks of cancer.Journal ArticleReviewSCOPUS: re.jinfo:eu-repo/semantics/publishe

Mixed response to chemotherapy in triple-negative breast cancer: A case report

Patients with breast cancer undergoing systemic therapies can have mixed response to treatment, with some lesions reducing their dimensions or also, in some cases, disappearing, and others progressing. Of note, breast cancer is an example of tumor heterogeneity, and this reflects the ability of the tumor to adapt to changing conditions and to overcome constraints to growth and dissemination. Hence, a mixed response to treatment may indicate that some clones have become resistant to the treatment and are triggering a disease progression. Nevertheless, a differential diagnosis should always be implemented when new lesions are detected, to rule out potential different etiologies. Too often subjects who received a prior diagnosis of cancer may face stigma of “cancer patients” although they have been successfully cured and have no evidence of residual disease. The systematic implementation of a sensible, appropriate differential diagnosis can help reduce the time to diagnosis and to treatment, with positive impact in patients’ outcomes and quality of life. Our case report describes the incidental finding of lung lesions in a woman treated for early breast cancer and highlights the importance of differential diagnosis in the specific subset of subjects who received a prior diagnosis of cancer.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

PIK3CA copy-number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer

As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations of PIK3CA represent the second most common alteration in TNBC after the TP53 mutation, with a prevalence of ∼10%–15%. Considering the well-established predictive role of PIK3CA mutations for response to agents targeting the PI3K/AKT/mTOR pathway, several clinical trials are currently evaluating these drugs in patients with advanced TNBC. However, much less is known regarding the actionability of PIK3CA copy-number gains, which represent a thoroughly common molecular alteration in TNBC, with a prevalence estimated at 6%–20%, and are listed as “likely gain-of-function” alterations in the OncoKB database. In the present paper, we describe two clinical cases in which patients harboring PIK3CA -amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value of PIK3CA amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on PIK3CA copy-number status, we urge for the introduction of PIK3CA amplification as a criterion for patient selection in future clinical trials in this setting.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer

The HER2-targeted antibody–drug conjugate trastuzumab emtansine (T-DM1) is approved for the treatment of metastatic, HER2-positive breast cancer after prior trastuzumab and taxane therapy, and has also demonstrated efficacy in the adjuvant setting in incomplete responders to neoadjuvant therapy. Despite its objective activity, intrinsic and acquired resistance to T-DM1 remains a major clinical challenge. T-DM1 mediates its activity in a number of ways, encompassing HER2 signalling blockade, Fc-mediated immune response and payload-mediated microtubule poisoning. Resistance mechanisms relating to each of these features have been demonstrated, and we outline the findings of these studies in this review. In our overview of the substantial literature on T-DM1 activity and resistance, we conclude that the T-DM1 resistance mechanisms most strongly supported by the experimental data relate to dysfunctional intracellular metabolism of the construct and subversion of DM1-mediated cell killing. Loss of dependence on signalling initiated by HER2–HER2 homodimers is not substantiated as a resistance mechanism by clinical or experimental studies, and the impact of EGFR expression and tumour immunological status requires further investigation. These findings are instructive with respect to strategies that might overcome T-DM1 resistance, including the use of second-generation anti-HER2 antibody–drug conjugates that deploy alternative linker-payload chemistries.SCOPUS: re.jinfo:eu-repo/semantics/publishe

FDG-PET/CT for Early Prediction of Response to Neoadjuvant Lapatinib, Trastuzumab, and Their Combination in HER2-positive Breast Cancer Patients: the Neo-ALTTO Study Results

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About an extrinsic gastric compression discovered during the workup of B12 deficiency

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Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group.

Patients with oligometastatic disease (OMD) often have controllable symptoms, and cures are possible. Technical improvements in surgery and radiotherapy have introduced the option of metastasis-directed ablative therapies as an adjunct or alternative to standard-of-care systemic therapies. Several clinical trials and registries are investigating the benefit of these therapeutic approaches across several cancer sites. This requires that patients are correctly included and followed with appropriate imaging. This article discusses the evidence and offers recommendations for the implementation of standard-of-care (Response Evaluation Criteria in Solid Tumours measurements on computed tomography [CT], magnetic resonance imaging [MRI] and bone scintigraphy) and advanced imaging modalities (functional, metabolic and radionuclide targeted) for identifying and following up patients with OMD. Imaging requirements for recognising OMD vary with tumour type, metastatic location, and timing of measurement in relation to previous treatment. At each point in the disease cycle (diagnosis, response assessment and follow-up), imaging must be tailored to the clinical question and the context of prior treatment. The differential use of whole-body approaches such as 18F-FDG-positron emission tomography (PET)/CT, diffusion-weighted MRI, 18F-Choline-PET/CT and 68Ga-prostate specific membrane antigen-PET/CT require rationalisation depending on clinical risk assessment. Optimal standardised imaging approaches will enable OMD trials to document patterns of disease progression and outcomes of treatment. Quality assured and quality controlled imaging data included in databases such as the European Organisation for Research and Treatment of Cancer Imaging platform for the Oligocare trial (a prospective, large-scale observational basket study being set up to collect outcome data from patients with OMD treated with radiation therapy) will establish a large and high-quality imaging warehouse for future research

N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium- 89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4- overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/ MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumabsensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4- masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.SCOPUS: ar.jinfo:eu-repo/semantics/publishe