Publications by authors named "Audrey Mauguen"

53 Publications

Diagnostic and Prognostic Utility of F-FDG PET/CT in Recurrent Salivary Gland Cancers.

AJR Am J Roentgenol 2021 Apr 7:1-13. Epub 2021 Apr 7.

Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065.

The role of F-FDG PET/CT in the evaluation of recurrent salivary gland tumors remains poorly defined. We investigated the diagnostic and prognostic utility of PET in this setting. A total of 146 patients with recurrent salivary gland cancer were treated at our institution between January 2002 and December 2015. Patients who underwent FDG PET/CT and conventional imaging (CT or MRI) within 3 months of recurrence ( = 78) were included in this retrospective analysis. On FDG PET/CT, we measured the SUV, total body metabolic tumor volume of all lesions, and total lesion glycolysis of all lesions to determine the intensity and extent of FDG-avid disease. We assessed the correlation of FDG PET/CT findings with clinicopathologic features, progression-free survival, and overall survival. FDG PET/CT was positive for recurrence in 74 of 78 patients (94.9%) and falsely negative in four patients (5.1%). In comparison with conventional imaging, FDG PET/CT performed for restaging detected additional recurrent lesions in 14 patients (17.9%). The median SUV was 7.4, the median total body metabolic tumor volume was 30.1 cm, and median total lesion glycolysis was 97.3 g/mL × cm. Sixty-six patients had progressive disease, and 54 died. Univariate and multivariate Cox hazards analysis identified pathologic risk group ( = .04), total body metabolic tumor volume ( < .001), and total lesion glycolysis ( < .001) as independent prognostic factors for progression-free survival and identified age ( = .05), total body metabolic tumor volume ( < .001), and total lesion glycolysis ( < .001) as independent prognostic factors for overall survival. In patients with recurrent salivary gland cancer, FDG PET/CT is useful as a single test for defining the extent of disease and providing prognostic information, which may help in selecting appropriate treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2214/AJR.20.23259DOI Listing
April 2021

Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses.

Blood Adv 2021 Jan;5(2):496-503

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.

Adoptive cell therapy using cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has demonstrated efficacy posttransplant. Despite the predicted limited engraftment of CMV-CTLs derived from third-party donors, partially matched third-party donor-derived CMV-CTLs have demonstrated similar response rates to those derived from primary hematopoietic cell transplantation donors. Little is known about the mechanisms through which adoptive cellular therapies mediate durable responses. We performed a retrospective analysis of patients receiving CMV-CTLs for treatment of CMV viremia and/or disease after allogeneic transplant between September of 2009 and January of 2018. We evaluated whether response to adoptively transferred CMV-CTLs correlated with immune reconstitution (IR), using validated CD4+ IR milestones of 50 × 106/L and 200 × 106/L. In this analysis, a cohort of 104 patients received CMV-CTLs derived from a primary transplant donor (n = 25), a third-party donor (n = 76), or both (n = 3). Response to therapy did not increase the likelihood of achieving CD4+ IR milestones at 1 (P = .53 and P > .99) or 2 months (P = .12 and P = .33). The origin of CMV-CTLs did not impact subsequent CD4+ IR. CMV-CTLs appeared to interact with host immunity in mediating responses. Recipients with a baseline CD4 >50 × 106/L had higher response to therapy (P = .02), improved overall survival (P < .001), and protection from CMV-related death (P = .002). Baseline endogenous immunity appears to improve CMV-related and overall survival in this cohort and can be an important marker at the initiation of therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839363PMC
January 2021

Preclinical and first-in-human-brain-cancer applications of [F]poly (ADP-ribose) polymerase inhibitor PET/MR.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa119. Epub 2020 Sep 15.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes.

Methods: We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry.

Results: In a preclinical mouse model, we illustrated that [F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen.

Conclusions: Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/noajnl/vdaa119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758909PMC
September 2020

Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression.

J Clin Oncol 2021 Jan 16;39(3):215-226. Epub 2020 Dec 16.

Departments of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Anti-GD2 monoclonal antibody (mAb) has proven efficacy in high-risk neuroblastoma (HR-NB). A small phase I GD2/GD3 vaccine trial (n = 15) described long-term survival and a favorable safety profile among patients with a history of disease progression (PD). The kinetics of mounting antibody response to vaccine and its prognostic impact on survival are now investigated in a phase II study (ClinicalTrials.gov identifier: NCT00911560).

Patients And Methods: One hundred two patients with HR-NB who achieved remission after salvage therapies were enrolled in this trial. They received seven subcutaneous injections of GD2/GD3 vaccine spanning 1 year plus oral β-glucan starting at week 6 after the third dose of vaccine. Serum anti-vaccine antibody titers were quantified by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms (SNPs) were determined by quantitative polymerase chain reaction. Kaplan-Meier and landmark Cox Regression models were used for survival estimates.

Results: Patients had a history of one (63%), two (21%), or three to six (16%) episodes of PD. 82% of them progressed following anti-GD2 mAb (m3F8/dinutuximab/naxitamab) therapy. Vaccine-related toxicities were self-limited injection-associated local reactions and fever without any > grade 3 toxicities. The progression-free survival (PFS) was 32% ± 6%, and the overall survival (OS) was 71% ± 7% at 5 years. Serum anti-GD2 (immunoglobulin G1 [IgG1] and IgM) and anti-GD3 (IgG1) titers showed notable increases following the initiation of β-glucan at week 6. There was an association between IgG1 titer and SNP rs3901533 of dectin-1, the β-glucan receptor. Multivariable analyses showed that anti-GD2-IgG1 titer ≥ 150 ng/mL by week 8 was associated with favorable PFS and OS, while having prior episodes of PD and the time from last PD to vaccine were associated with PFS.

Conclusion: GD2/GD3 vaccine plus β-glucan elicited robust antibody responses in patients with HR-NB with prior PD. Higher anti-GD2-IgG1 titer was associated with improved survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.01892DOI Listing
January 2021

Poly(ADP-ribose)polymerase1: A potential molecular marker to identify cancer during colposcopy procedures.

J Nucl Med 2020 Nov 13. Epub 2020 Nov 13.

Memorial Sloan Kettering Cancer Center, United States.

Despite efforts in prevention, cervical cancer still presents with a high worldwide incidence and remains a great problem in public health, especially in low-income countries. Screening programs, such as colposcopy with Papanicolaou testing, have greatly improved mortality rates. However, the agents currently used to delineate those lesions (topical application of acetic acid and/or Lugol's iodine) lack specificity and sometimes can lead to unnecessary biopsies or even cervical excisions. A tool to enable in vivo histology to quickly and quantitatively distinguish between tumor, dysplastic and healthy tissue would be of great clinical interest. Here we describe the use of PARPi-FL, a fluorescent imaging agent that targets PARP1, a nuclear enzyme that is overexpressed in cancer when compared to the normal surrounding tissues. We exploit its use as an optical imaging agent to specifically target PARP1 expression, which was demonstrated to be higher in cervical cancer when compared to the normal surrounding tissue. After its topical application on freshly excised cone biopsies, the nuclei of tumor cells emitted a specific fluorescent signal that could be visualized using a hand-held fluorescence confocal microscope. This approach has the potential to improve in vivo identification of tumor cells during colposcopy examination allowing a rapid, non-invasive, and accurate histopathological assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.120.253575DOI Listing
November 2020

Important Concerns Over SARS-CoV-2 Infection in Children With Cancer-Reply.

JAMA Oncol 2020 Oct 15. Epub 2020 Oct 15.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.4767DOI Listing
October 2020

Association of Known Melanoma Risk Factors with Primary Melanoma of the Scalp and Neck.

Cancer Epidemiol Biomarkers Prev 2020 Nov 20;29(11):2203-2210. Epub 2020 Aug 20.

School of Population and Global Health, The University of Western Australia, Perth, Western Australia, Australia.

Background: Scalp and neck (SN) melanoma confers a worse prognosis than melanoma of other sites but little is known about its determinants. We aimed to identify associations between SN melanoma and known risk genes, phenotypic traits, and sun exposure patterns.

Methods: Participants were cases from the Western Australian Melanoma Health Study ( = 1,200) and the Genes, Environment, and Melanoma Study ( = 3,280). Associations between risk factors and SN melanoma, compared with truncal and arm/leg melanoma, were investigated using binomial logistic regression. Facial melanoma was also compared with the trunk and extremities, to evaluate whether associations were subregion specific, or reflective of the whole head/neck region.

Results: Compared with other sites, increased odds of SN and facial melanoma were observed in older individuals [SN: OR = 1.28, 95% confidence interval (CI) = 0.92-1.80, = 0.016; Face: OR = 4.57, 95% CI = 3.34-6.35, < 0.001] and those carrying -rs12203592*T (SN: OR = 1.35, 95% CI = 1.12-1.63, = 0.002; Face: OR = 1.29, 95% CI = 1.10-1.50, = 0.001). Decreased odds were observed for females (SN: OR = 0.49, 95% CI = 0.37-0.64, < 0.001; Face: OR = 0.66, 95% CI = 0.53-0.82, < 0.001) and the presence of nevi (SN: OR = 0.66, 95% CI = 0.49-0.89, = 0.006; Face: OR = 0.65, 95% CI = 0.52-0.83, < 0.001).

Conclusions: Differences observed between SN melanoma and other sites were also observed for facial melanoma. Factors previously associated with the broader head and neck region, notably older age, may be driven by the facial subregion. A novel finding was the association of -rs12203592 with both SN and facial melanoma.

Impact: Understanding the epidemiology of site-specific melanoma will enable tailored strategies for risk factor reduction and site-specific screening campaigns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-0595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641988PMC
November 2020

Head-to-Head Evaluation of F-FES and F-FDG PET/CT in Metastatic Invasive Lobular Breast Cancer.

J Nucl Med 2021 Mar 17;62(3):326-331. Epub 2020 Jul 17.

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.

Invasive lobular carcinoma (ILC) demonstrates lower conspicuity on F-FDG PET than the more common invasive ductal carcinoma. Other molecular imaging methods may be needed for evaluation of this malignancy. As ILC is nearly always (95%) estrogen receptor (ER)-positive, ER-targeting PET tracers such as 16α-F-fluoroestradiol (F-FES) may have value. We reviewed prospective trials at Memorial Sloan Kettering Cancer Center using F-FES PET/CT to evaluate metastatic ILC patients with synchronous F-FDG and F-FES PET/CT imaging, which allowed a head-to-head comparison of these 2 PET tracers. Six prospective clinical trials using F-FES PET/CT in patients with metastatic breast cancer were performed at Memorial Sloan Kettering Cancer Center from 2008 to 2019. These trials included 92 patients, of whom 14 (15%) were of ILC histology. Seven of 14 patients with ILC had F-FDG PET/CT performed within 5 wk of the research F-FES PET/CT and no intervening change in management. For these 7 patients, the F-FES and F-FDG PET/CT studies were analyzed to determine the total number of tracer-avid lesions, organ systems of involvement, and SUV of each organ system for both tracers. In the 7 comparable pairs of scans, there were a total of 254 F-FES-avid lesions (SUV, 2.6-17.9) and 111 F-FDG-avid lesions (SUV, 3.3-9.9) suggestive of malignancy. For 5 of 7 (71%) ILC patients, F-FES PET/CT detected more metastatic lesions than F-FDG PET/CT. In the same 5 of 7 patients, the SUV of F-FES-avid lesions was greater than the SUV of F-FDG-avid lesions. One patient had F-FES-avid metastases with no corresponding F-FDG-avid metastases. There were no patients with F-FDG-avid distant metastases without F-FES-avid distant metastases, although in one patient liver metastases were evident on F-FDG but not on F-FES PET. F-FES PET/CT compared favorably with F-FDG PET/CT for detection of metastases in patients with metastatic ILC. Larger prospective trials of F-FES PET/CT in ILC should be considered to evaluate ER-targeted imaging for clinical value in patients with this histology of breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.120.247882DOI Listing
March 2021

Comparison of efficacy and toxicity of intravitreal melphalan formulations for retinoblastoma.

PLoS One 2020 1;15(7):e0235016. Epub 2020 Jul 1.

Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America.

Objective: Intravitreal melphalan injections are commonly used in the treatment for intraocular retinoblastoma. This study compares retinal toxicity and ocular survival between two formulations, with and without propylene glycol (Alkeran vs. Evomela, respectively).

Methods: A retrospective cohort study of retinoblastoma patients who received intravitreal injections of Alkeran and Evomela at 30 μg from September 2012 to January 2019 at a single tertiary care center were enrolled. Retinal toxicity was measured using electroretinogram (ERG) and compared using a multivariate analysis of 338 injections in 101 eyes of 96 patients. Ocular survival of 163 eyes in 150 patients was compared across formulations using Cox proportional hazards model. Eyes were censored at the time a patient received a dose other than 30 μg.

Results: Overall, ERG decline (mean, 95% CI) for each injection was -5.58 μV (-7.17, -3.99). No significant differences in ERG decrement were found between Alkeran (with alcohol) -5.52uV (-6.99, -4.05). and Evomela (without alcohol) -5.65uV (-8.31 to -2.98) formulations (p = 0.93). Ocular survival at 24 months was 93.6% (95% CI 86.2, 97.1) with alcohol and 91.7% (95% CI 53.9, 98.8) without alcohol. The hazard ratio (HR) for without vs with alcohol was 0.50 (95% CI 0.06 to 4.07); no significant difference in ocular survival was found between formulations (p = 0.52).

Conclusions And Relevance: No differences were found in retinal toxicity and ocular survival between 30 μg intravitreal injections of Alkeran or Evomela for intraocular retinoblastoma. Given the increased stability of Evomela, intravitreal treatment could be expanded to centers without the ability to supply Alkeran due to its shorter safety window; however, Alkeran is less expensive. For those with existing infrastructure, Alkeran is a comparable, cost-effective alternative.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235016PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329086PMC
September 2020

COVID-19 in Children With Cancer in New York City.

JAMA Oncol 2020 09;6(9):1459-1460

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.2028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221844PMC
September 2020

Low toxicity and favorable overall survival in relapsed/refractory B-ALL following CAR T cells and CD34-selected T-cell depleted allogeneic hematopoietic cell transplant.

Bone Marrow Transplant 2020 11 10;55(11):2160-2169. Epub 2020 May 10.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T-cell therapy, we retrospectively reviewed pediatric/young adult patients with relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1-20 years) with a median potential follow-up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0-37%), 20% (95% CI: 0-40%), and 80% (95% CI: 60-100%), respectively. Severe toxicity following CAR T cells did not impact OS (p = 0.27), while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T-cell depleted (TCD; n = 9) vs unmodified (n = 6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24 months was 22% (95% CI: 0-49%) vs 0% (p = 0.14), 0% vs 50% [95% CI: 10-90%] (p = 0.02) and 100% vs 50% [95% CI: 10-90%] (p = 0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared with unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0926-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606268PMC
November 2020

Baseline FDG-PET/CT detects bone marrow involvement in follicular lymphoma and provides relevant prognostic information.

Blood Adv 2020 04;4(8):1812-1823

Molecular Imaging and Therapy Service, Department of Radiology.

In follicular lymphoma (FL), detection of bone marrow (BM) involvement (BMI) by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) improves the accuracy of staging vs BM biopsy (BMB) alone. Our objective was to determine the diagnostic utility of PET for BMI FL and the prognostic value of BMI by PET (positive PET result [PET+]). Records of patients (2002-2016) with PET and BMB at the time of initial treatment were reviewed. BMI was identified by positive BMB result (BMB+) and/or unifocal or multifocal BM FDG uptake on blindly reviewed PET scans with no corresponding CT abnormality (PET+). Among 261 patients, BMI was diagnosed in 78 patients (29.9%) by PET+, in 81 patients (31.0%) by BMB+, and in 113 patients (43.3%) by either PET+ or BMB+. PET+ upstaged 24 patients to stage IV, including 10 from stages I or II to stage IV. Median duration of follow-up was 6.0 years (range, 0-16.6 years). In univariate analysis, a high Follicular Lymphoma International Prognosis Index (FLIPI) score, PET+, and BMB+ correlated with shorter progression-free survival (PFS; all P ≤ .03), and high FLIPI, PET+, and combined PET+ and BMB+ with shorter overall survival (OS; all P ≤ .01). In multivariate analysis, PET+ was the only independent predictor of PFS, whereas high FLIPI score and PET+ predicted OS (P ≤ .03). Combined PET and BMB identify BMI more accurately than either BMB or PET alone, but BMB rarely adds critical information. For patients initiating treatment of FL, identification of BMI by PET is predictive of PFS and OS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020001579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189280PMC
April 2020

Safety and Feasibility of PARP1/2 Imaging with F-PARPi in Patients with Head and Neck Cancer.

Clin Cancer Res 2020 07 3;26(13):3110-3116. Epub 2020 Apr 3.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with F-PARPi in patients with head and neck cancer.

Patients And Methods: Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection. Static PET/CT scans were obtained at 30, 60, and 120 minutes postinjection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry, and complete blood count were obtained before and after tracer administration.

Results: F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, F-PARPi had focal uptake in all primary lesions ( = 10, SUV = 2.8 ± 1.2) and all F-FDG-positive lymph nodes ( = 34). F-PARPi uptake was seen in F-FDG-negative lymph nodes of 3 patients ( = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with F-FDG. The overall effective dose with F-PARPi PET was 3.9 mSv - 5.2 mSv, contrast was high [SUV(lesion)/SUV(trapezius muscle) = 4.5] and less variable than F-FDG when compared with the genioglossus muscle (1.3 vs. 6.0, = 0.001).

Conclusions: Imaging of head and neck cancer with F-PARPi is feasible and safe. F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-3484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7421489PMC
July 2020

The geriatric syndrome of sarcopenia impacts allogeneic hematopoietic cell transplantation outcomes in older lymphoma patients.

Leuk Lymphoma 2020 08 31;61(8):1833-1841. Epub 2020 Mar 31.

Department of Medicine, Weill Cornell Medical College, New York, NY, USA.

Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1742909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429343PMC
August 2020

Validation of the use of a fluorescent PARP1 inhibitor for the detection of oral, oropharyngeal and oesophageal epithelial cancers.

Nat Biomed Eng 2020 03 12;4(3):272-285. Epub 2020 Mar 12.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

For oral, oropharyngeal and oesophageal cancer, the early detection of tumours and of residual tumour after surgery are prognostic factors of recurrence rates and patient survival. Here, we report the validation, in animal models and a human, of the use of a previously described fluorescently labelled small-molecule inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) for the detection of cancers of the oral cavity, pharynx and oesophagus. We show that the fluorescent contrast agent can be used to quantify the expression levels of PARP1 and to detect oral, oropharyngeal and oesophageal tumours in mice, pigs and fresh human biospecimens when delivered topically or intravenously. The fluorescent PARP1 inhibitor can also detect oral carcinoma in a patient when applied as a mouthwash, and discriminate between fresh biopsied samples of the oral tumour and the surgical resection margin with more than 95% sensitivity and specificity. The PARP1 inhibitor could serve as the basis of a rapid and sensitive assay for the early detection and for the surgical-margin assessment of epithelial cancers of the upper intestinal tract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41551-020-0526-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136849PMC
March 2020

Testing tumors from different anatomic sites for clonal relatedness using somatic mutation data.

Biometrics 2021 Mar 2;77(1):283-292. Epub 2020 Apr 2.

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.

A common task for the cancer pathologist is to determine, in a patient suffering from cancer, whether a new tumor in a distinct anatomic site from the primary is an independent occurrence of cancer or a metastasis. As mutational profiling of tumors becomes more widespread in routine clinical practice, this diagnostic task can be greatly enhanced by comparing mutational profiles of the tumors to determine if they are sufficiently similar to conclude that the tumors are clonally related, that is, one is a metastasis of the other. We present here a likelihood ratio test for clonal relatedness in this setting and provide evidence of its validity. The test is unusual in that there are two possible alternative hypotheses, representing the two anatomic sites from which the single clonal cell could have initially emerged. Although evidence for clonal relatedness is largely provided by the presence of exact mutational matches in the two tumors, we show that it is possible to observe data where the test is statistically significant even when no matches are observed. This can occur when the mutational profile of one of the tumors is closely aligned with the anatomic site of the other tumor, suggesting indirectly that the tumor originated in that other site. We exhibit examples of this phenomenon and recommend a strategy for interpreting the results of these tests in practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/biom.13256DOI Listing
March 2021

TOXICITY AND EFFICACY OF INTRAVITREAL MELPHALAN FOR RETINOBLASTOMA: 25 µg Versus 30 µg.

Retina 2021 Jan;41(1):208-212

Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York.

Purpose: To compare retinal toxicity as measured by electroretinogram, ocular, and patient survival in retinoblastoma treated with intravitreal melphalan at two concentrations (25 vs. 30 µg).

Methods: Single-center, retrospective analysis of retinoblastoma eyes receiving 25-µg or 30-µg intravitreal melphalan from September 2012 to January 2019. Ocular toxicity was measured by electroretinogram of evaluable injections in 449 injections in 136 eyes. A repeated-measures linear mixed model with a random intercept and slope was applied to account for repeated measures for each eye.

Results: Average decline in electroretinogram after each additional injection was -4.9 µV (95% confidence interval -6.3 to -3.4); electroretinogram declined by -4.6 µV (95% confidence interval -7.0 to -2.2) after 25-µg injections and -5.2 µV (95% confidence interval -6.6 to -3.8) after 30-µg injections (P = 0.66). Injection at a new clock site hour was associated with a -3.91-µV lower average (95% confidence interval -7.8 to -0.04).

Conclusion: Electroretinogram-measured toxicity in retinoblastoma eyes treated with intravitreal injections was not found to be different across 25-µg and 30-µg injections. There were no cases of extraocular extension or metastatic deaths in our patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IAE.0000000000002782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483207PMC
January 2021

C-Choline PET/CT in Recurrent Prostate Cancer: Retrospective Analysis in a Large U.S. Patient Series.

J Nucl Med 2020 06 20;61(6):827-833. Epub 2019 Dec 20.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York

Our purpose was to evaluate the performance of C-choline PET/CT in detecting biochemically recurrent prostate cancer (PCa) in a large non-European cohort (in the context of emerging evidence for prostate-specific membrane antigen PET in this setting) and to map patterns of PCa recurrence. We retrospectively analyzed C-choline PET/CT scans from 287 patients who were enrolled in an imaging protocol based on rising prostate-specific antigen (PSA) levels (mean, 3.43 ng/mL; median, 0.94 ng/mL; range, 0.15-89.91 ng/mL) and suspected recurrent PCa. A total of 187 patients had undergone primary radical prostatectomy (RP) (79/187 had secondary radiotherapy), 30 had undergone primary radiotherapy, and 70 had a persistent PSA elevation after receiving initial treatment (69 after RP, 1 after radiotherapy). The level of suspicion for recurrence on C-choline PET/CT was scored (0, negative; 1, equivocal; 2, positive) by 2 readers. The correlation between C-choline PET/CT positivity and initial treatment, Gleason score, National Comprehensive Cancer Network stage, PSA level, PSA doubling time, PSA velocity, and time between initial treatment and PET imaging was evaluated. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were used to map C-choline recurrence patterns. Considering scores 1 and 2 as positives, consensus between the 2 readers deemed 66% of the C-choline PET/CT scans as positive. When sorted by PSA level, 45% of patients with a PSA of less than 0.5 ng/mL, 56% of patients with a PSA of 0.5-0.99 ng/mL, 70% of patients with a PSA of 1.0-1.99 ng/mL, and 90% of patients with a PSA of at least 2.0 ng/mL scored either 1 or 2 on C-choline PET/CT scans. When considering scores of 2 only, C-choline PET/CT positivity was 54% (28%, 46%, 62%, and 81%, respectively, for patients with PSA < 0.5 ng/mL, 0.5-0.99 ng/mL, 1.0-1.99 ng/mL, and ≥ 2.0 ng/mL). In multivariate analysis, only PSA level was significantly associated with scan positivity. Pattern analysis showed that pelvic lymph nodes were the most common site of recurrence, and 28% of patients had C-choline-positive suspected recurrences outside the initial treatment field. C-choline PET/CT can detect PCa recurrence even among patients with low PSA levels when interpretation accounts for the clinical context, providing a certain pretest probability. Until prostate-specific membrane antigen agents are fully approved for PCa, choline PET/CT may provide clinical utility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.119.233098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262219PMC
June 2020

An EM algorithm to improve the estimation of the probability of clonal relatedness of pairs of tumors in cancer patients.

BMC Bioinformatics 2019 Nov 8;20(1):555. Epub 2019 Nov 8.

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Ave, 2nd floor, New York, NY, 10017, USA.

Background: We previously introduced a random-effects model to analyze a set of patients, each of which has two distinct tumors. The goal is to estimate the proportion of patients for which one of the tumors is a metastasis of the other, i.e. where the tumors are clonally related. Matches of mutations within a tumor pair provide the evidence for clonal relatedness. In this article, using simulations, we compare two estimation approaches that we considered for our model: use of a constrained quasi-Newton algorithm to maximize the likelihood conditional on the random effect, and an Expectation-Maximization algorithm where we further condition the random-effect distribution on the data.

Results: In some specific settings, especially with sparse information, the estimation of the parameter of interest is at the boundary a non-negligible number of times using the first approach, while the EM algorithm gives more satisfactory estimates. This is of considerable importance for our application, since an estimate of either 0 or 1 for the proportion of cases that are clonal leads to individual probabilities being 0 or 1 in settings where the evidence is clearly not sufficient for such definitive probability estimates.

Conclusions: The EM algorithm is a preferable approach for our clonality random-effect model. It is now the method implemented in our R package Clonality, making available an easy and fast way to estimate this model on a range of applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12859-019-3148-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839069PMC
November 2019

Restaging [F] fludeoxyglucose positron emission tomography/computed tomography scan in recurrent cutaneous squamous cell carcinoma: Diagnostic performance and prognostic significance.

J Am Acad Dermatol 2020 Apr 25;82(4):878-886. Epub 2019 Sep 25.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Background: There are no specific recommendations for [F] fludeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in assessing recurrent cutaneous squamous cell carcinoma (cSCC).

Objective: To evaluate FDG-PET/CT in recurrent cSCC.

Methods: FDG-PET/CT scans were retrospectively reviewed. Sites of abnormal uptake were noted and correlated with biopsy/histopathology studies, where available, and with follow-up imaging or clinical data in others. Comparison with available CT/magnetic resonance imaging was performed. The prognostic significance of PET/CT parameters was evaluated, and PET/CT-based change in management was recorded.

Results: A total of 115 FDG-PET/CT scans were analyzed in 100 consecutive patients with cSCC. Of these, 96 (84%) scans were positive for recurrence, and 25 showed distant metastases. PET/CT detected unsuspected disease sites in 39 of 115 scans (34%), locoregional disease in 14, distant metastases in 11, both locoregional disease and distant metastases in 8, additional local cutaneous disease in 5, and second malignancy in 1. Comparison of 78 PET/CT scans with available CT/magnetic resonance imaging showed 37 additional abnormalities on 23 PET/CT scans, predominantly including skin/subcutaneous lesions and nodes. PET/CT led to change in management in 28% of patients. On univariate/multivariate analysis, increased number of FDG-positive lesions and lung metastases on PET/CT was associated with increased risk of death/disease progression.

Limitations: Retrospective study.

Conclusions: FDG-PET/CT was sensitive in detecting recurrent disease in cSCC, led to change in management for 28% of patients, and proved to be of prognostic value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2019.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549433PMC
April 2020

Testing clonal relatedness of two tumors from the same patient based on their mutational profiles: update of the Clonality R package.

Bioinformatics 2019 11;35(22):4776-4778

Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10017, USA.

Summary: The Clonality R package is a practical tool to assess the clonal relatedness of two tumors from the same patient. We have previously presented its functionality for testing tumors using loss of heterozygosity data or copy number arrays. Since then somatic mutation data have been more widely available through next generation sequencing and we have developed new methodology for comparing the tumors' mutational profiles. We thus extended the package to include these two new methods for comparing tumors as well as the mutational frequency estimation from external data required for their implementation. The first method is a likelihood ratio test that is readily available on a patient by patient basis. The second method employs a random-effects model to estimate both the population and individual probabilities of clonal relatedness from a group of patients with pairs of tumors. The package is available on Bioconductor.

Availability And Implementation: Bioconductor (http://bioconductor.org/packages/release/bioc/html/Clonality.html).

Supplementary Information: Supplementary data are available at Bioinformatics online.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btz486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853680PMC
November 2019

Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel Fusion-Driven Cancer.

Cancer Discov 2019 05 15;9(5):605-616. Epub 2019 Mar 15.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.

Despite the important role of the PI3K/AKT/mTOR axis in the pathogenesis of cancer, to date there have been few functional oncogenic fusions identified involving the genes. A 12-year-old female with a histopathologically indeterminate epithelioid neoplasm was found to harbor a novel fusion between the and genes. Through expanded use access, she became the first pediatric patient to be treated with the oral ATP-competitive pan-AKT inhibitor ipatasertib. Treatment resulted in dramatic tumor regression, demonstrating through patient-driven discovery that the fusion resulted in activation of AKT1, was an oncogenic driver, and could be therapeutically targeted with clinical benefit. Post-clinical validation using patient-derived model systems corroborated these findings, confirmed a membrane-bound and constitutively active fusion protein, and identified potential mechanisms of resistance to single-agent treatment with ipatasertib. SIGNIFICANCE: This study describes the patient-driven discovery of the first AKT1 fusion-driven cancer and its treatment with the AKT inhibitor ipatasertib. Patient-derived and model systems are used to confirm the fusion as a tumorigenic driver and identify potential mechanisms of resistance to AKT inhibition..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-18-0953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497560PMC
May 2019

Total retinal detachments due to retinoblastoma: Outcomes following intra-arterial chemotherapy/ophthalmic artery chemosurgery.

PLoS One 2018 26;13(4):e0195395. Epub 2018 Apr 26.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

Purpose: To report on the rate and timing of retinal reattachment and outcomes for retinoblastoma children who have total retinal detachments at presentation to our center and were treated with intra-arterial chemotherapy (ophthalmic artery chemosurgery, OAC).

Patients And Methods: Single-center retrospective review of retinoblastoma patients who presented with total retinal detachments and were subsequently treated with OAC at MSKCC between May 2006 and July 2016. Endpoints were retinal detachment resolution, visual function, ERG amplitude, ocular survival, and patient survival from metastases.

Results: 87 eyes of 84 retinoblastoma patients were included. Using a survival multistate model, by 36 months of follow-up, there was a 54% cumulative probability of complete retinal reattachment and a 76% probability of partial reattachment. 24% of eyes that completely reattached received only OAC without any prior or adjuvant treatments. Eyes that completely reattached were significantly more likely to have been diagnosed at a younger age (p<0.0001) and to have greater initial ERG values (p = 0.006). At final follow-up, 14% of eyes had gained at least 25 μV of ERG activity, and 8.0% had achieved hand motion vision or better, including one to 20/60. 13% of eyes were enucleated. No patient died from metastatic disease, and only one developed metastases.

Conclusion: OAC can successfully treat previously considered "non-salvageable" retinoblastoma eyes with total retinal detachments, promote retinal reattachment in the majority of eyes, and preserve ocular and patient survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195395PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919618PMC
July 2018

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34 hematopoietic progenitor cells in patients with sickle cell disease: interim results.

Haematologica 2018 05 1;103(5):770-777. Epub 2018 Feb 1.

Sickle Cell Program, Division of Hematology, Albert Einstein College of Medicine, Bronx, NY, USA

Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cells that can be harvested for transduction or gene editing. We therefore performed a phase I dose-escalation study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34 cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and ten were on hydroxyurea. Of eight patients who achieved a CD34 cell concentration >30 cells/μL, six were on hydroxyurea. There was no clear dose response to increasing plerixafor dosage. There was a low rate of serious adverse events; two patients developed vaso-occlusive crises, at the doses of 80 μg/kg and 240 μg/kg. Hydroxyurea may have contributed to the limited CD34 mobilization by affecting baseline peripheral blood CD34 counts, which correlated strongly with peak peripheral blood CD34 counts. Plerixafor administration did not induce significant increases in the fraction of activated neutrophils, monocytes, or platelets. However, increased neutrophils positive for activated β2 integrin and Mac-1 were associated with serious adverse events. In summary, plerixafor was well tolerated but did not achieve consistent CD34 cell mobilization in this cohort of patients, most of whom were being actively treated with hydroxyurea and only one was chronically transfused. The study will continue with escalation of the dose of plerixafor and modification of hydroxyurea administration. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2017.187047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927989PMC
May 2018

Contralateral breast cancers: Independent cancers or metastases?

Int J Cancer 2018 01 28;142(2):347-356. Epub 2017 Sep 28.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.

A cancer in the contralateral breast in a woman with a previous or synchronous breast cancer is typically considered to be an independent primary tumor. Emerging evidence suggests that in a small subset of these cases the second tumor represents a metastasis. We sought to investigate the issue using massively parallel sequencing targeting 254 genes recurrently mutated in breast cancer. We examined the tumor archives at Memorial Sloan Kettering Cancer Center for the period 1995-2006 to identify cases of contralateral breast cancer where surgery for both tumors was performed at the Center. We report results from 49 patients successfully analyzed by a targeted massively parallel sequencing assay. Somatic mutations and copy number alterations were defined by state-of-the-art algorithms. Clonal relatedness was evaluated by statistical tests specifically designed for this purpose. We found evidence that the tumors in contralateral breasts were clonally related in three cases (6%) on the basis of matching mutations at codons where somatic mutations are rare. Clinical data and the presence of similar patterns of gene copy number alterations were consistent with metastasis for all three cases. In three additional cases, there was a solitary matching mutation at a common PIK3CA locus. The results suggest that a subset of contralateral breast cancers represent metastases rather than independent primary tumors. Massively parallel sequencing analysis can provide important evidence to clarify the diagnosis. However, given the inter-tumor mutational heterogeneity in breast cancer, sufficiently large gene panels need to be employed to define clonality convincingly in all cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.31051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749409PMC
January 2018

Defining Cancer Subtypes With Distinctive Etiologic Profiles: An Application to the Epidemiology of Melanoma.

J Am Stat Assoc 2017 3;112(517):54-63. Epub 2017 May 3.

Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.

We showcase a novel analytic strategy to identify sub-types of cancer that possess distinctive causal factors, i.e. sub-types that are "etiologically" distinct. The method involves the integrated analysis of two types of study design: an incident series of cases with double primary cancers with detailed information on tumor characteristics that can be used to define the sub-types; a case-series of incident cases with information on known risk factors that can be used to investigate the specific risk factors that distinguish the sub-types. The methods are applied to a rich melanoma dataset with detailed information on pathologic tumor factors, and comprehensive information on known genetic and environmental risk factors for melanoma. Identification of the optimal sub-typing solution is accomplished using a novel clustering analysis that seeks to maximize a measure that characterizes the distinctiveness of the distributions of risk factors across the sub-types and that is a function of the correlations of tumor factors in the case-specific tumor pairs. This analysis is challenged by the presence of extensive missing data. If successful, studies of this nature offer the opportunity for efficient study design to identify unknown risk factors whose effects are concentrated in defined sub-types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01621459.2016.1191499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460661PMC
May 2017

Estimating the probability of clonal relatedness of pairs of tumors in cancer patients.

Biometrics 2018 03 8;74(1):321-330. Epub 2017 May 8.

Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, 2nd Floor, New York, New York 10017, U.S.A.

Next generation sequencing panels are being used increasingly in cancer research to study tumor evolution. A specific statistical challenge is to compare the mutational profiles in different tumors from a patient to determine the strength of evidence that the tumors are clonally related, that is, derived from a single, founder clonal cell. The presence of identical mutations in each tumor provides evidence of clonal relatedness, although the strength of evidence from a match is related to how commonly the mutation is seen in the tumor type under investigation. This evidence must be weighed against the evidence in favor of independent tumors from non-matching mutations. In this article, we frame this challenge in the context of diagnosis using a novel random effects model. In this way, by analyzing a set of tumor pairs, we can estimate the proportion of cases that are clonally related in the sample as well as the individual diagnostic probabilities for each case. The method is illustrated using data from a study to determine the clonal relationship of lobular carcinoma in situ with subsequent invasive breast cancers, where each tumor in the pair was subjected to whole exome sequencing. The statistical properties of the method are evaluated using simulations, demonstrating that the key model parameters are estimated with only modest bias in small samples in most configurations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/biom.12710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677588PMC
March 2018

Joint model imputation to estimate the treatment effect on long-term survival using auxiliary events.

J Biopharm Stat 2017 20;27(6):1043-1053. Epub 2017 Mar 20.

a Univ. Bordeaux ISPED , Centre INSERM U1219-Epidémiologie-Biostatistique , Bordeaux , France.

Clinical trial duration may be a concern in clinical research, especially in cancer trials where the endpoint is overall survival. A surrogate endpoint can be used as an auxiliary variable to analyze the treatment effect earlier. At an early time point, the high number of censored observations can be compensated by the imputation of the unobserved deaths times. We propose to use predictions of the risk of death from a joint model for a recurrent event and a terminal event, which account for disease relapse information. Two imputation methods were compared: sampling from the estimated parametric distribution of the survival time and sampling using its nonparametric estimation. The treatment effect and its standard error were estimated via multiple imputations. The performances of the two methods were compared in terms of bias in the estimates, standard errors, and coverage probability. Both methods were then retrospectively applied to two randomized clinical trials studying the effect of adjuvant chemotherapy in breast cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10543406.2017.1295249DOI Listing
July 2018

Clonal relationships between lobular carcinoma in situ and other breast malignancies.

Breast Cancer Res 2016 06 23;18(1):66. Epub 2016 Jun 23.

Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Background: Recent evidence suggests that lobular carcinoma in situ (LCIS) can be a clonal precursor of invasive breast cancers of both the ductal and lobular phenotypes. We sought to confirm these findings with an extensive study of fresh frozen breast specimens from women undergoing mastectomy.

Methods: Patients with a history of LCIS presenting for therapeutic mastectomy were identified prospectively. Frozen tissue blocks were collected, screened for lesions of interest, and subjected to microdissection and DNA extraction. Copy number profiling, whole-exome sequencing, or both were performed. Clonal relatedness was assessed using specialized statistical techniques developed for this purpose.

Results: After exclusions for genotyping failure, a total of 84 lesions from 30 patients were evaluated successfully. Strong evidence of clonal relatedness was observed between an LCIS lesion and the invasive cancer for the preponderance of cases with lobular carcinoma. Anatomically distinct in situ lesions of both ductal and lobular histology were also shown to be frequently clonally related.

Conclusions: These data derived from women with LCIS with or without invasive cancer confirm that LCIS is commonly the clonal precursor of invasive lobular carcinoma and that distinct foci of LCIS frequently share a clonal origin, as do foci of LCIS and ductal carcinoma in situ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13058-016-0727-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918003PMC
June 2016