Publications by authors named "Karen Cadoo"

50 Publications

Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: an Open-Label, Four-Arm, Phase II Study.

Clin Cancer Res 2021 Oct 13. Epub 2021 Oct 13.

Medicine, Memorial Sloan Kettering Cancer Center.

This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer. Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, Phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate. Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progression-free survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade {greater than or equal to}3 adverse events across all cohorts were neutropenia (45/94 [47.9%] patients), anemia (31/94 [33.0%]), thrombocytopenia (30/94 [31.9%]), and diarrhea and vomiting (10/94 [10.6%] each). Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1-3, 8-10, and 15-17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0158DOI Listing
October 2021

Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination.

NPJ Breast Cancer 2021 Oct 11;7(1):135. Epub 2021 Oct 11.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4-5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.
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http://dx.doi.org/10.1038/s41523-021-00339-0DOI Listing
October 2021

The effects of neoadjuvant chemotherapy and interval debulking surgery on body composition in patients with ovarian cancer.

JCSM Clin Rep 2021 Jan 11;6(1):11-16. Epub 2020 Nov 11.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: The aim of this study was to quantify changes in body composition during ovarian cancer treatment and relate these changes to rates of complete gross resection (CGR).

Methods: One hundred two patients with stage III or IV ovarian cancer who underwent neoadjuvant chemotherapy (NACT) followed by interval debulking surgery were a part of a prospectively collected database that included computed tomography scans at three time points-diagnosis, following NACT, and following debulking surgery. Skeletal muscle, visceral adipose, and subcutaneous adipose tissue volumes were obtained from a 30-mm volumetric slab beginning at the third lumbar vertebrae.

Results: Following NACT, skeletal muscle volume was significantly reduced (352.5 to 335.0 cm, < 0.001), whereas adiposity was unchanged. Body mass index (BMI) and skeletal muscle volume were significantly lower in patients who achieved CGR ( < 0.05). When these patients were stratified by BMI, the significant association of skeletal muscle to CGR was limited to patients with a BMI < 25 kg/m ( = 0.007).

Conclusion: Skeletal muscle volume was significantly reduced in patients undergoing NACT for ovarian cancer. Non-overweight patients were more likely to achieve CGR if they had lower skeletal muscle volume. Use of volumetric-based measurement for ascertaining body composition should be explored further.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415724PMC
January 2021

Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.

Nat Cancer 2021 Mar 15;2:357-365. Epub 2021 Feb 15.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, New York, 10065, USA.

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.
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http://dx.doi.org/10.1038/s43018-021-00172-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294573PMC
March 2021

Uptake and acceptability of a mainstreaming model of hereditary cancer multigene panel testing among patients with ovarian, pancreatic, and prostate cancer.

Genet Med 2021 Jul 13. Epub 2021 Jul 13.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: To address demands for timely germline information to guide treatments, we evaluated experiences of patients with ovarian, pancreatic, and prostate cancer with a mainstreaming genetic testing model wherein multigene panel testing was ordered by oncologists with standardized pretest patient education, and genetic counselors delivered results and post-test genetic counseling via telephone.

Methods: Among 1,203 eligible patients, we conducted a prospective single-arm study to examine patient uptake and acceptability (via self-report surveys at baseline and three weeks and three months following result return) of this mainstreaming model.

Results: Only 10% of eligible patients declined participation. Among 1,054 tested participants, 10% had pathogenic variants (PV), 16% had variants of uncertain significance (VUS), and 74% had no variant identified (NV). Participants reported high initial acceptability, including high satisfaction with their testing decision. Variability over time in several outcomes existed for participants with PV or NV: those with NV experienced a temporary increase in depression (p < 0.001; p < 0.001), and those with PV experienced a small increase in genetic testing distress (p = 0.03). Findings suggested that result type, sex, and cancer type were also associated with outcomes including clinical depression and uncertainty.

Conclusion: This mainstreaming model may offer a feasible approach for extending access to germline genetic information.
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http://dx.doi.org/10.1038/s41436-021-01262-2DOI Listing
July 2021

Prevalence and Characterization of Biallelic and Monoallelic and Variant Carriers From a Pan-Cancer Patient Population.

JCO Precis Oncol 2021 26;5. Epub 2021 Feb 26.

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

and have been implicated as autosomal recessive cancer predisposition genes. Although individuals with biallelic and pathogenic variants (PVs) have increased cancer and polyposis risk, risks for monoallelic carriers are uncertain. We sought to assess the prevalence and characterize and from a large pan-cancer patient population.

Materials And Methods: Patients with pan-cancer (n = 11,081) underwent matched tumor-normal sequencing with consent for germline analysis. Medical records and tumors were reviewed and analyzed. Prevalence of PVs was compared with reference controls (Genome Aggregation Database).

Results: -PVs were identified in 40 patients including 39 monoallelic carriers (39/11,081 = 0.35%) and one with biallelic variants (1/11,081 = 0.009%) and a diagnosis of isolated early-onset breast cancer. -associated mutational signature 30 was identified in the tumors of the biallelic patient and two carriers. Colonic polyposis was not identified in any patient. -PVs were identified in 13 patients, including 12 monoallelic carriers (12/11,081 = 0.11%) and one with biallelic variants (1/11,081 = 0.009%) and diagnoses of later-onset cancers, attenuated polyposis, and abnormal MSH3-protein expression. Of the 12 carriers, two had early-onset cancer diagnoses with tumor loss of heterozygosity of the wild-type allele. Ancestry-specific burden tests demonstrated that and prevalence was not significantly different in this pan-cancer population versus controls.

Conclusion: and germline alterations were not enriched in this pan-cancer patient population. However, tumor-specific findings, such as mutational signature 30 and loss of heterozygosity of the wild-type allele, suggest the potential contribution of monoallelic variants to tumorigenesis in a subset of patients.
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http://dx.doi.org/10.1200/PO.20.00443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232072PMC
February 2021

Therapeutic Implications of Germline Testing in Patients With Advanced Cancers.

J Clin Oncol 2021 Aug 16;39(24):2698-2709. Epub 2021 Jun 16.

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

Purpose: Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer.

Methods: Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype-directed therapy were determined.

Results: Among 11,947 patients across > 50 malignancies, 17% (n = 2,037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; < 1% level 4). variants accounted for 42% of therapeutically actionable findings, followed by (13%), (12%), mismatch repair genes (11%), and (5%). When limited to the 9,079 patients with metastatic or recurrent cancer, 8% (n = 710) harbored level 1 or 3B genetic findings and 3.2% (n = 289) received germline genotype-directed therapy. Germline genotype-directed therapy was received by 61% and 18% of metastatic cancer patients with level 1 and level 3B findings, respectively, and by 54% of , 75% of mismatch repair, 43% of , 35% of , 24% of , and 19% of carriers. Of patients receiving a poly(ADP-ribose) polymerase inhibitor, 45% (84 of 188) had tumors other than breast or ovarian cancer, wherein the drug, at time of delivery, was delivered in an investigational setting.

Conclusion: In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype-directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.
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http://dx.doi.org/10.1200/JCO.20.03661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376329PMC
August 2021

Mesonephric and mesonephric-like carcinomas of the female genital tract: molecular characterization including cases with mixed histology and matched metastases.

Mod Pathol 2021 08 26;34(8):1570-1587. Epub 2021 Mar 26.

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

Mesonephric carcinoma of the cervix is a rare tumor derived from Wolffian remnants. Mesonephric-like carcinomas of the ovary and endometrium, while morphologically similar, do not have obvious Wolffian derivation. Here, we sought to characterize the repertoire of genetic alterations in primary mesonephric and mesonephric-like carcinomas, in the distinct histologic components of mixed cases, as well as in matched primary tumors and metastases. DNA from microdissected tumor and normal tissue from mesonephric carcinomas (cervix, n = 8) and mesonephric-like carcinomas (ovarian n = 15, endometrial n = 13) were subjected to sequencing targeting 468 cancer-related genes. The histologically distinct components of four cases with mixed histology and four primary tumors and their matched metastases were microdissected and analyzed separately. Mesonephric-like carcinomas were underpinned by somatic KRAS mutations (25/28, 89%) akin to mesonephric carcinomas (8/8, 100%), but also harbored genetic alterations more frequently reported in Müllerian tumors. Mesonephric-like carcinomas that lacked KRAS mutations harbored NRAS (n = 2, ovary) or BRAF (n = 1, endometrium) hotspot mutations. PIK3CA mutations were identified in both mesonephric-like (8/28, 28%) and mesonephric carcinomas (2/8, 25%). Only mesonephric-like tumors harbored CTNNB1 hotspot (4/28, 14%) and PTEN (3/13, 23%) mutations. Copy number analysis revealed frequent gains of chromosomes 1q and 10 in both mesonephric (87% 1q; 50% chromosome 10) and mesonephric-like tumors (89% 1q; 43% chromosome 10). Chromosome 12 gains were more frequent in ovarian mesonephric-like carcinomas, and losses of chromosome 9 were more frequent in mesonephric than in mesonephric-like carcinomas (both p = 0.01, Fisher's exact test). The histologically distinct components of four mixed cases were molecularly related and shared similar patterns of genetic alterations. The progression from primary to metastatic lesions involved the acquisition of additional mutations, and/or shifts from subclonal to clonal mutations. Our findings suggest that mesonephric-like carcinomas are derived from a Müllerian substrate with differentiation along Wolffian/mesonephric lines.
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http://dx.doi.org/10.1038/s41379-021-00799-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343944PMC
August 2021

Outcomes of incidentally detected ovarian cancers diagnosed at time of risk-reducing salpingo-oophorectomy in BRCA mutation carriers.

Gynecol Oncol 2021 05 10;161(2):521-526. Epub 2021 Mar 10.

Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA; Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; HOPe Directorate, St. James's Hospital, Dublin, Ireland. Electronic address:

Objective: Prior data suggested that women with incidentally detected occult invasive ovarian cancer (OIOC) at the time of risk-reducing salpingo-oophorectomy (RRSO) for BRCA mutation may have poorer prognoses than would be expected based on disease stage. We sought to evaluate prevalence and outcomes of patients with OIOC in a tertiary referral center.

Methods: Patients with BRCA mutation undergoing RRSO from 01/2005 to 05/2017 were identified, and their records reviewed. Women with incidentally detected OIOC were included; those with clinical features raising preoperative suspicion for malignancy were excluded.

Results: 548 patients with BRCA mutation who underwent RRSO were identified. 26 (4.7%) had an OIOC (median age 55 years; range 42-75); 15(58%) patients, BRCA1; 9(34%), BRCA2; 2(8%) had a mutation in both genes. All OIOCs were high-grade serous: 10 (38%) Stage I; 8 (31%) Stage II; 8(31%) Stage III. 24(92%) patients received adjuvant platinum/taxane therapy. Of Stage III patients, 4 (50%) were identified intraoperatively; the remaining 4 (50%) had microscopic nodal disease on final pathology only. At median follow-up of 67.3 months (28-166) no Stage I patients have recurred; 2 Stage II and 6 Stage III patients recurred. 5-year progression-free survival (PFS) was 72% (95%CI, 50.2-85.7%); median PFS for the cohort was 129 months (95%CI, 75.3-not estimable). 5-year disease-specific survival (DSS) was 96% (95%CI, 76-99%); median DSS not reached.

Conclusion: Consistent with prior reports, almost 5% of patients had an OIOC at RRSO. The majority with early-stage disease had excellent PFS and DSS outcomes, as would be expected based on disease stage.
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http://dx.doi.org/10.1016/j.ygyno.2021.02.006DOI Listing
May 2021

Clonal relationship and directionality of progression of synchronous endometrial and ovarian carcinomas in patients with DNA mismatch repair-deficiency associated syndromes.

Mod Pathol 2021 05 16;34(5):994-1007. Epub 2020 Dec 16.

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

Sporadic synchronous endometrial (ECs) and ovarian cancers (OCs), although clinically considered to be independent primaries, have been shown to be clonally related and likely constitute metastases from each other. We sought to define whether synchronous ECs/OCs in patients with DNA mismatch repair (MMR)-deficiency syndromes would be clonally related. We subjected synchronous ECs/OCs from four patients (LS3-LS6) with clinically confirmed Lynch syndrome (LS) and one patient with constitutional mismatch repair-deficiency syndrome (CMMRD) to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutations, copy number alterations (CNAs), clonal relatedness and clonal decomposition analyses were performed using previously described bioinformatics methods. All synchronous ECs/OCs analyzed were considered independent primaries based on clinicopathologic criteria. Sequencing analysis revealed that the ECs/OCs of three cases (LS2-CMMRD, L3, L4) harbored similar repertoires of somatic mutations and CNAs and were clonally related. In these three cases, a subset of subclonal mutations in the EC became clonal in the OC, suggesting that the EC was likely the substrate from which the OC developed. LS5's EC/OC had distinct mutational profiles but shared specific CNAs. In contrast, LS6's EC/OC harbored distinct somatic mutations and lacked CNAs, consistent with each tumor constituting an independent primary lesion. In LS5 and LS6, PTEN mutations and PTEN loss of protein expression were found to be restricted to the EC. Finally, re-analysis of sequencing data of sporadic synchronous ECs/OCs supported the observations made in the current study that the directionality of progression is likely from the endometrium to the ovary. In conclusion, contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent distinct primary tumors. A subset of MMR-deficiency syndrome-related synchronous ECs/OCs, however, may originate from a single primary tumor at variance with their clinical diagnosis, with the endometrium being the likeliest site of origin.
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http://dx.doi.org/10.1038/s41379-020-00721-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076061PMC
May 2021

A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers.

Gynecol Oncol 2021 01 1;160(1):71-76. Epub 2020 Nov 1.

Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America. Electronic address:

Purpose: Selinexor, a selective inhibitor of nuclear export, monotherapy causes nuclear accumulation of tumor-suppressor proteins and has anti-tumor activity in ovarian and endometrial cancers. The safety and tolerability of oral selinexor plus intravenous carboplatin and paclitaxel chemotherapy (selinexor + CP) was evaluated in this population.

Patients And Methods: This phase I, 3 + 3 dose-escalation study assessed 4 selinexor + CP regimens. Patients in cohorts of 3, regardless of disease type, were administered 1 of 4 alternating regimens (selinexor at 30 mg/m or 60 mg plus CP at AUC 5 and 175 mg/m or 80 mg/m, respectively) for 6-10 cycles (1 cycle = 21 days), followed by selinexor maintenance. Enrolled patients with ovarian cancer had received 1 prior platinum-based therapy. Patients with endometrial cancer were chemotherapy-naive or had received 1 prior platinum-based therapy. Response was evaluated every 9 weeks.

Results: Twenty-three patients were treated (5 serous ovarian cancer; 18 endometrial cancer, including 6 carcinosarcomas). The most common treatment-related adverse events (TRAEs) were thrombocytopenia (100%), leukopenia (91%), and hyperglycemia (87%). The most common grade 3/4 TRAEs were leukopenia (70%), neutropenia (70%), lymphopenia (61%), anemia (57%), and alanine transaminase increase (43%). One treatment-related dose-limiting toxicity (grade 3 syncope) occurred. Twelve patients achieved a partial response and 1 achieved a complete response. Responses to all four regimens were observed in ovarian and endometrial cancers.

Conclusions: Combination selinexor + CP was safe and tolerated in advanced ovarian and endometrial cancers.
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http://dx.doi.org/10.1016/j.ygyno.2020.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779742PMC
January 2021

Machine learning-based prediction of microsatellite instability and high tumor mutation burden from contrast-enhanced computed tomography in endometrial cancers.

Sci Rep 2020 10 20;10(1):17769. Epub 2020 Oct 20.

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

To evaluate whether radiomic features from contrast-enhanced computed tomography (CE-CT) can identify DNA mismatch repair deficient (MMR-D) and/or tumor mutational burden-high (TMB-H) endometrial cancers (ECs). Patients who underwent targeted massively parallel sequencing of primary ECs between 2014 and 2018 and preoperative CE-CT were included (n = 150). Molecular subtypes of EC were assigned using DNA polymerase epsilon (POLE) hotspot mutations and immunohistochemistry-based p53 and MMR protein expression. TMB was derived from sequencing, with > 15.5 mutations-per-megabase as a cut-point to define TMB-H tumors. After radiomic feature extraction and selection, radiomic features and clinical variables were processed with the recursive feature elimination random forest classifier. Classification models constructed using the training dataset (n = 105) were then validated on the holdout test dataset (n = 45). Integrated radiomic-clinical classification distinguished MMR-D from copy number (CN)-low-like and CN-high-like ECs with an area under the receiver operating characteristic curve (AUROC) of 0.78 (95% CI 0.58-0.91). The model further differentiated TMB-H from TMB-low (TMB-L) tumors with an AUROC of 0.87 (95% CI 0.73-0.95). Peritumoral-rim radiomic features were most relevant to both classifications (p ≤ 0.044). Radiomic analysis achieved moderate accuracy in identifying MMR-D and TMB-H ECs directly from CE-CT. Radiomics may provide an adjunct tool to molecular profiling, especially given its potential advantage in the setting of intratumor heterogeneity.
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http://dx.doi.org/10.1038/s41598-020-72475-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575573PMC
October 2020

Mutations, Homologous DNA Repair Deficiency, Tumor Mutational Burden, and Response to Immune Checkpoint Inhibition in Recurrent Ovarian Cancer.

JCO Precis Oncol 2020 16;4. Epub 2020 Jun 16.

Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Homologous DNA repair-deficient (HRD) ovarian cancers (OCs), including those with mutations, have higher levels of genetic instability, potentially resulting in higher immunogenicity, and have been suggested to respond better to immune checkpoint inhibitors (ICIs) than homologous DNA repair-proficient OCs. However, clinical evidence is lacking. The study aimed to evaluate the associations between mutations, HRD, and other genomic parameters and response to ICIs and survival in OC.

Methods: This is a single-institution retrospective analysis of women with recurrent OC treated with ICIs. mutation status and clinicopathologic variables were abstracted from the medical records. Targeted and whole-exome sequencing data available for a subset of patients were used to assess tumor mutational burden (TMB), HRD, and fraction of genome altered (FGA). ICI response was defined as lack of disease progression for ≥ 24 weeks. Associations of status and genomic alterations with progression-free survival (PFS) and overall survival (OS) were determined using Cox proportional hazards models.

Results: Of the 143 women treated with ICIs, 134 had known mutation status. Deleterious germline or somatic mutations were present in 31 women (24%). There was no association between presence of mutations and response ( = .796) or survival. Genomic analysis in 73 women found no association between TMB ( = .344) or HRD ( = .222) and response, PFS, or OS. There were also no significant differences in somatic genetic alterations between responders and nonresponders. High FGA was associated with an improvement in PFS ( = .014) and OS ( = .01).

Conclusion: TMB, mutations, and HRD are not associated with response or survival, cautioning against their use as selection criteria for ICI in recurrent OC. FGA should be investigated further as a biomarker of response to immunotherapy in OC.
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http://dx.doi.org/10.1200/PO.20.00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446408PMC
June 2020

Prevalence of pancreaticobiliary cancers in Irish families with pathogenic BRCA1 and BRCA2 variants.

Fam Cancer 2021 04 12;20(2):97-101. Epub 2020 Sep 12.

School of Medicine, Trinity College Dublin, Dublin, Ireland.

Pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are associated with an increased lifetime risk of pancreatic ductal adenocarcinoma (PDAC), and more recently have been associated with increased risk of biliary tract cancers (BTC). This study assessed the prevalence, age and gender distribution of PDAC/BTC cases in families known to carry a BRCA1/2 PV compared to those of the Irish population. A review of all families referred to a national genetics clinic from 09/11/1997 to 01/06/2018 was performed. The BOADICEA algorithm was used to estimate the probability that an untested relative of a known BRCA1/2 PV carrier with PDAC was a carrier. We reviewed 3252 family pedigrees, 1193 contained a proband who underwent testing for BRCA1/2 based on Manchester score ≥ 15. Among 128 BRCA2 PV-positive families, 27 (21%) contained a 1st/2nd/3rd-degree relative with PDAC, while of 116 BRCA1 PV-positive families, 11 (9%) contained a 1st/2nd/3rd-degree relative with PDAC. Within these 38 families, 25 patients with PDAC had ≥ 50% likelihood of being a BRCA1/2 PV carrier. This cohort had a median age at diagnosis of 55 years (range 33-75), with a mean (55 years) lower than 8364 patients with PDAC identified through the National Cancer Registry of Ireland (71 years, p < 0.0001). Six BRCA2 positive (5%) and 2 BRCA1 positive pedigrees (2%) included an individual with BTC; median age at diagnosis was 65 years (range 33-99). PDAC and BTC are prevalent in Irish families harbouring a BRCA2 PV and are associated with early-onset malignancy. This supports current guidelines recommending universal germline testing for PDAC patients.
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http://dx.doi.org/10.1007/s10689-020-00205-1DOI Listing
April 2021

Endometrial Cancers in or Germline Mutation Carriers: Assessment of Homologous Recombination DNA Repair Defects.

JCO Precis Oncol 2019 29;3. Epub 2019 Aug 29.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Endometrial cancer (EC) is not considered a component of the hereditary breast and ovarian cancer syndrome but can arise in patients with germline (g) mutations. Biallelic alterations are associated with genomic features of homologous recombination DNA repair deficiency (HRD) in cancer. We sought to determine if ECs in g mutation carriers harbor biallelic alterations and/or features of HRD.

Methods: Of 769 patients with EC who underwent germline panel testing, 10 pathogenic g mutation carriers were identified, and their tumor- and normal-derived DNA was subjected to massively parallel sequencing targeting at least 410 cancer-related genes. Three g-associated ECs were identified in 232 ECs subjected to whole-exome sequencing by The Cancer Genome Atlas. Somatic mutations, copy number alterations, loss of heterozygosity, microsatellite instability (MSI), and genomic HRD features were assessed.

Results: Of the 13 patients included who had EC, eight harbored pathogenic g mutations and five harbored g mutations. Eight (100%) and two (40%) ECs harbored biallelic and alterations through loss of heterozygosity of the wild-type allele. All ECs harbored somatic mutations. One monoallelic/sporadic g-associated EC had promoter methylation and was MSI high. High large-scale state transition scores, a genomic feature of HRD, were found only in ECs with bi- but not monoallelic alterations. The Signature Multivariate Analysis HRD signature Sig3 was enriched in biallelic g ECs, and the three ECs from The Cancer Genome Atlas with biallelic alterations subjected to whole-exome sequencing displayed a dominant HRD-related mutational signature 3.

Conclusion: A subset of g-associated ECs harbor biallelic alterations and genomic features of HRD, which may benefit from homologous recombination-directed treatment regimens. ECs in mutation carriers might be sporadic and even MSI high, and may potentially benefit from immune-checkpoint inhibition.
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http://dx.doi.org/10.1200/PO.19.00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446423PMC
August 2019

Utility of serum CA-125 monitoring in patients with ovarian cancer undergoing immune checkpoint inhibitor therapy.

Gynecol Oncol 2020 08 2;158(2):303-308. Epub 2020 Jun 2.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weil Cornell Medical College, New York, NY, USA. Electronic address:

Objective: This study aimed to evaluate the utility of serum cancer antigen-125 (CA-125) levels to monitor patients with epithelial ovarian cancer (EOC) undergoing immune checkpoint inhibitor (ICI) therapy.

Method: This was a single-center retrospective review of all patients with EOC who were treated with ICI therapy from January 2013 to May 2017. This study compared the percentage change in baseline CA-125 in patients who had clinical benefit, defined as complete response, partial response, or stable disease by RECIST 1.1, with duration ≥24 weeks, versus those who did not. The groups were compared by Wilcoxon rank-sum test.

Results: Fifty-nine (66%) of 89 patients who underwent ICI therapy had CA-125 data at baseline and during treatment. Of those who derived clinical benefit, 11/15 (73%) experienced an increase in CA-125 from baseline to end of treatment. Of those who did not derive clinical benefit, 36/44 (82%) experienced a CA-125 increase (p = 0.48). The average % increase from baseline to within 12 weeks of treatment initiation for patients with and without clinical benefit was 34% and 195%, respectively (p = 0.008).

Conclusion: Our analysis demonstrates a statistically significant difference in the magnitude of increase in CA-125 levels within the first 12 weeks of treatment between patients who achieved clinical benefit and those who did not. However, both groups of patients were equally likely to experience an increase in CA-125 within 12 weeks. These findings suggest that physicians should apply caution when using early CA-125 data to guide treatment decisions for patients with EOC undergoing ICI therapy.
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http://dx.doi.org/10.1016/j.ygyno.2020.04.710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423717PMC
August 2020

Clinical patterns and genomic profiling of recurrent 'ultra-low risk' endometrial cancer.

Int J Gynecol Cancer 2020 06 5;30(6):717-723. Epub 2020 May 5.

Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Objective: Despite good prognosis for patients with low-risk endometrial cancer, a small subset of women with low-grade/low-stage endometrial cancer experience disease recurrence and death. The aim of this study was to characterize clinical features and mutational profiles of recurrent, low-grade, non-myoinvasive, 'ultra-low risk' endometrioid endometrial adenocarcinomas.

Methods: We retrospectively identified patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA endometrioid endometrial cancers who underwent primary surgery at our institution, between January 2009 and February 2017, with follow-up of ≥12 months. 'Ultra-low risk' was defined as FIGO tumor grade 1, non-myoinvasive, and lacking lymphovascular space invasion. Tumor-normal profiling using massively parallel sequencing targeting 468 genes was performed. Microsatellite instability was assessed using MSIsensor. DNA mismatch repair (MMR) protein proficiency was determined by immunohistochemistry.

Results: A total of 486 patients with ultra-low risk endometrioid endometrial cancers were identified: 14 (2.9%) of 486 patients developed a recurrence. Median follow-up for non-recurrent endometrioid endometrial cancers: 34 (range 12-116) months; for recurrent endometrioid endometrial cancers: 50.5 (range 20-116) months. Patients with recurrent disease were older, had lower body mass index, and were most commonly non-White (p=0.025, p<0.001, and p<0.001, respectively). Other clinical characteristics did not differ. MMR immunohistochemistry was obtained for 211 (43%) tumors: 158 (75%) MMR-proficient and 53 (25%) MMR-deficient. Primary tumors of 9 recurrent and 27 non-recurrent endometrioid endometrial cancers underwent mutational profiling. Most were microsatellite stable (6/9, 67% recurrent; 25/27, 93% non-recurrent). Recurrent and mutations were present in both groups. Exon 3 hotspot mutations were found in 4/9 (44%) recurrent and 8/27 (30%) non-recurrent (p=0.44).

Conclusions: Patients diagnosed with ultra-low risk endometrioid endometrial cancers have an overall excellent prognosis. However, in our study, 2.9% of patients with no identifiable clinical or pathologic risk factors developed recurrence. Further work is warranted to elucidate the mechanism for recurrence in this population.
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http://dx.doi.org/10.1136/ijgc-2020-001241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295026PMC
June 2020

Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family.

Fam Cancer 2020 10;19(4):315-322

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), 10833 Le Conte Ave, Los Angeles, CA, 90095, USA.

Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome. Classification and interpretation of intronic variants, especially those outside the consensus ± 1 ~ 2 splice sites are challenging as it is uncertain whether such variants would affect splicing accuracy and efficiency. The assessment of the pathogenicity of splice site variants in MLH1 is further complicated by the various isoforms due to alternative splicing. In this report, we describe a 42-year-old female with Lynch syndrome who carries a germline variant, MLH1 c.678-3T>A, in the splice acceptor site of intron 8. Functional studies and semiquantitative analysis demonstrated that this variant causes a significant increase in the transcripts with exon 9 or exon 9 and 10 deletions, which presumably leads to premature protein truncation or abnormal protein. In addition, we also observed MSI-H and loss of MLH1 by IHC in patient's tumor tissue. This variant also segregated with Lynch Syndrome related cancers in three affected family members. Based on these evidence, the MLH1 c.678-3T>A variant is considered pathogenic.
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http://dx.doi.org/10.1007/s10689-020-00180-7DOI Listing
October 2020

11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood.

Cancer 2020 07 22;126(13):3114-3121. Epub 2020 Apr 22.

Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown.

Methods: Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients).

Results: Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration.

Conclusions: Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.
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http://dx.doi.org/10.1002/cncr.32907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383476PMC
July 2020

A phase 1 dose-escalation study of intraperitoneal cisplatin, intravenous/intraperitoneal paclitaxel, bevacizumab, and olaparib for newly diagnosed ovarian cancer.

Gynecol Oncol 2020 04 17;157(1):214-221. Epub 2020 Jan 17.

Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065, United States of America; Department of Medicine, Weill Cornell Medical College, 1300 York Ave., New York, NY 10021, United States of America.

Objective: We assessed the safety and maximum tolerated dose (MTD) of the poly ADP-ribose polymerase (PARP) inhibitor olaparib with intravenous (IV)/intraperitoneal (IP) cisplatin/paclitaxel and IV bevacizumab, followed by olaparib and bevacizumab maintenance, in patients with newly diagnosed ovarian cancer who had undergone primary debulking surgery.

Methods: Treatment included: (Cycles 1-6) Day 1, IV paclitaxel 135 mg/m/3 h + (from Cycle 2 onward) bevacizumab 15 mg/kg; Day 2, IP cisplatin 75 mg/m; Days 2-8, olaparib (50/100/200 mg BID); Day 8, IP paclitaxel 60 mg/m of a 21-day cycle. Maintenance (Cycles 7-22) included: olaparib 300 mg BID and bevacizumab 15 mg/kg Day 1. The primary endpoint was MTD of olaparib, chemotherapy, and bevacizumab.

Results: Seventeen women were treated (Cohort 1 [50 mg olaparib], 8 patients; Cohort 2 [100 mg], 3 patients; and Cohort 3 [200 mg], 6 patients). Median age was 57 years (47-73); 94% had stage III disease; 29% had a germline BRCA mutation. Two of 6 patients in Cohort 3 experienced a dose-limiting toxicity (DLT). Grade 3/4 toxicities included: neutropenia (56%), lymphopenia (31%), anemia (25%), and fatigue (19%). Most patients started (88%, 81%) and completed (75%, 50%) maintenance olaparib and bevacizumab, respectively; 36% of patients on olaparib maintenance required a dose reduction. Median PFS was 33 months (26.2-NA).

Conclusions: The MTD of intermittently dosed olaparib with concurrent IV/IP cisplatin/paclitaxel and bevacizumab is 100 mg BID. Non-hematologic toxicities were predominantly low grade. One-third of patients on olaparib maintenance required dose reduction.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127949PMC
April 2020

Cancer Susceptibility Mutations in Patients With Urothelial Malignancies.

J Clin Oncol 2020 02 3;38(5):406-414. Epub 2019 Dec 3.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors.

Patients And Methods: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database.

Results: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were (n = 9; 1.5%), (n = 8; 1.4%), (n = 8; 1.4%), (n = 6; 1.0%), (n = 4; 0.7%), and and (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% 6% in those without variants; = .01). and were significantly associated with an increased risk for UC (odds ratio, 3.7 [ = .004] and 4.6 [ = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants.

Conclusion: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.
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http://dx.doi.org/10.1200/JCO.19.01395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351337PMC
February 2020

Clinical outcomes of patients with POLE mutated endometrioid endometrial cancer.

Gynecol Oncol 2020 01 19;156(1):194-202. Epub 2019 Nov 19.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA. Electronic address:

Objectives: Assess outcomes of a clinical cohort of patients with endometrioid endometrial cancer (EEC) harboring somatic POLE exonuclease domain mutations (EDMs).

Methods: Patients were consented to a protocol of tumor-normal massively parallel sequencing of 410-468 cancer related genes. EECs subjected to sequencing from 2014 to 2018 were reviewed. Tumors with somatic POLE EDMs were identified. EECs were assessed for microsatellite instability (MSI) using MSIsensor and immunohistochemical analysis for mismatch repair (MMR) proteins.

Results: Of the 451 EECs sequenced, 23 had a POLE EDM (5%): 20 primary and 3 recurrent tumors sequenced. Nineteen cases (83%) were stage I/II and 4 (17%) were stages III/IV. Thirteen EECs (57%) were of FIGO grades 1/2, 10 (43%) grade 3. All patients were treated with surgery and 17 (89%) received adjuvant therapy. Five (22%) demonstrated loss of DNA MMR protein expression, none were due to Lynch syndrome. MSIsensor scores were conclusive for 21 samples: 19 were microsatellite stable and 2 MSI-high. After median follow-up of 30 months, 4/23 (17%) developed recurrences: 3 with initial grade 3 stage I and 1 with grade 1 stage III disease. One patient with grade 2 stage IV EEC had progressive disease after treatment.

Conclusions: Patients with POLE EDM EEC have been shown to have a favorable prognosis. In this real-world cohort of patients, de novo metastatic disease and recurrences in initially uterine-confined cases were observed. Further research is warranted before incorporating the presence of POLE EDM into decision-making regarding adjuvant therapy.
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http://dx.doi.org/10.1016/j.ygyno.2019.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980651PMC
January 2020

Sentinel lymph node mapping alone compared to more extensive lymphadenectomy in patients with uterine serous carcinoma.

Gynecol Oncol 2020 01 16;156(1):70-76. Epub 2019 Nov 16.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. Electronic address:

Objectives: The objective of our study was to assess survival among patients with uterine serous carcinoma (USC) undergoing sentinel lymph node (SLN) mapping alone versus patients undergoing systematic lymphadenectomy (LND).

Methods: We retrospectively reviewed patients undergoing primary surgical treatment for newly diagnosed USC at our institution from 1/1/1996-12/31/2017. Patients were assigned to either SLN mapping alone (SLN cohort) or systematic LND without SLN mapping (LND cohort). Progression-free (PFS) and overall survival (OS) were estimated using Kaplan-Meier method, compared using Logrank test.

Results: 245 patients were available for analysis: 79 (32.2%) underwent SLN, 166 (67.7%) LND. 132 (79.5%) in the LND cohort had paraaortic LND (PALND) versus none in the SLN cohort. Median age: 66 and 68 years in the SLN and LND cohorts, respectively (p>0.05). Proportion of stage I/II disease: 67.1% (n = 53) and 64.5% (n = 107) in the SLN and LND cohorts, respectively (p>0.05). Median follow-up: 23 (range, 1-96) and 66 months (range, 4-265) in the SLN and LND cohorts, respectively (p < 0.001). Two-year OS in stage I/II disease (n = 160, 60.1%): 96.6% (SE ± 3.4) and 89.6% (SE ± 2.2) in the SLN and LND cohorts, respectively (p = 0.8). Two-year OS in stage III disease (n = 77): 73.6% (SE ± 10.2) and 77.3% (SE ± 5.8) in the SLN and LND cohorts, respectively (p = 0.8).

Conclusions: SLN mapping alone and systematic LND yielded similar survival outcomes in stage I-III USC. In our practice, the SLN algorithm has replaced systematic LND as the primary staging modality in this setting.
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http://dx.doi.org/10.1016/j.ygyno.2019.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980657PMC
January 2020

The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

NPJ Breast Cancer 2019 1;5:38. Epub 2019 Nov 1.

25University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, TX USA.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of or . These three variants were also studied functionally by measuring survival and chromosome fragility in patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44,  = 0.034 and OR = 3.79;  = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for :p.Arg658* and found that also :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96;  = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat -associated tumors.
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http://dx.doi.org/10.1038/s41523-019-0127-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825205PMC
November 2019

Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma.

Hum Mutat 2020 01 3;41(1):103-109. Epub 2019 Sep 3.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York.

Fumarate hydratase (FH) mutations underpin the autosomal recessive syndrome. FH deficiency and the autosomal dominant syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH c.1431_1433dupAAA (p.Lys477dup) genomic alteration has been conclusively shown to contribute to FH deficiency when occurring with another FH germline alteration. However, a sufficiently large dataset has been lacking to conclusively determine its clinical significance to cancer predisposition in the heterozygous state. We reviewed a series of 7,571 patients with cancer who received germline results through MSK-IMPACT testing at the Memorial Sloan Kettering Cancer Center. The FH c.1431_1433dupAAA (p.Lys477dup) variant was detected in 24 individuals, none of whom was affected with renal cancer. Eleven of the 372 patients with renal cancer were identified to carried pathogenic FH variants associated with HLRCC. None of these 372 patients with renal cancer carried the FH c.1431_1433dupAAA variant. Our data indicate the FH c.1431_1433dupAAA is not associated with cancer including renal cell carcinoma.
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http://dx.doi.org/10.1002/humu.23900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930334PMC
January 2020

Brain metastasis in epithelial ovarian cancer by BRCA1/2 mutation status.

Gynecol Oncol 2019 07 18;154(1):144-149. Epub 2019 May 18.

Weill Cornell Medical College of Cornell University, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Objective: To evaluate clinical outcomes of patients with BRCA-associated ovarian cancer who developed brain metastases (BM).

Methods: Patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC) and BM, treated at a single institution from 1/1/2008-7/1/2018, were identified from two institutional databases. Charts and medical records were retrospectively reviewed for clinical characteristics and germline BRCA mutation status. Appropriate statistics were used.

Results: Of 3649 patients with EOC, 91 had BM (2.5%). Germline mutation status was available for 63 (69%) cases; 21 (35%) of these harbored a BRCA1/2 mutation (15 BRCA1, 6 BRCA2). Clinical characteristics were similar between groups. BM were diagnosed at a median of 31 months (95% CI, 22.6-39.4) in BRCA-mutated (mBRCA) and 32 months (95% CI, 23.7-40.3) in wild-type BRCA (wtBRCA) (p = 0.78) patients. Brain metastases were the only evidence of disease at time of BM diagnoses in 48% (n = 10) mBRCA and 19% (n = 8) wtBRCA (p = 0.02) patients. There was no difference in treatment of BM by mutation status (p = 0.84). Survival from time of BM diagnosis was 29 months (95%CI, 15.5-42.5) in mBRCA and 9 months (95% CI, 5.5-12.5) in wtBRCA patients, with an adjusted hazard ratio (HR) of 0.53, p = 0.09; 95% CI, 0.25-1.11. HR was adjusted for presence of systemic disease at time of BM diagnosis.

Conclusion: This is the largest study to date comparing outcomes in patients with EOC and BM by mutation status. mBRCA patients were more likely to have isolated BM, which may be a factor in their long survival. This supports the pursuit of aggressive treatment for mBRCA EOC patients with BM. Additional studies examining the correlation of BRCA mutational status with BM are warranted.
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http://dx.doi.org/10.1016/j.ygyno.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589378PMC
July 2019

First-in-Human Phase I Study of the Activin A Inhibitor, STM 434, in Patients with Granulosa Cell Ovarian Cancer and Other Advanced Solid Tumors.

Clin Cancer Res 2019 Sep 8;25(18):5458-5465. Epub 2019 May 8.

Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: STM 434 is a soluble receptor ligand trap targeting activin A, a protein in the TGFβ family that plays important roles in growth, differentiation, and cancer cachexia. This study evaluated the safety, antitumor activity, and metabolic effects of STM 434 in a first-in-human, multicenter, phase I clinical trial (NCT02262455).

Patients And Methods: Patients with advanced solid tumors were enrolled in 8 dose cohorts ranging from 0.25 mg/kg every 4 weeks to 8 mg/kg every 2 weeks via a 3 + 3 dose-escalation design. The primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included safety, pharmacokinetics, and response. As activin A is implicated in metabolism and muscle function, changes in key metabolic parameters, including lean body mass and 6-minute walk test, were serially measured.

Results: Thirty-two patients were treated on study. The most common treatment-related adverse events were fatigue (41%) and mucocutaneous bleeding complications including epistaxis (34%) and gingival bleeding (22%), likely related to off-target inhibition of bone morphogenetic protein 9 (BMP9). STM 434 treatment resulted in the expected follicle-stimulating hormone level decreases in most patients and in metabolic parameter changes, including an increase in total lean body mass and 6-minute walk test distance. No responses were observed in the 30 evaluable patients, but the stable disease rate in patients with granulosa cell ovarian cancer was 10 of 12 (80%).

Conclusions: Although no direct antitumor efficacy was documented, potentially clinically meaningful dose-related metabolic effects, including treatment of cancer cachexia, were observed that support further exploration of activin A inhibitors that limit BMP9 blockade..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899078PMC
September 2019

Retreatment with carboplatin and paclitaxel for recurrent endometrial cancer: A retrospective study of the Memorial Sloan Kettering Cancer Center experience.

Gynecol Oncol Rep 2019 May 5;28:120-123. Epub 2019 Apr 5.

Memorial Sloan Kettering Cancer Center, Department of Medicine, Gynecologic Medical Oncology Service, 300 East 66 St, New York, NY 10065, USA.

Women with endometrial cancer (EC) frequently receive adjuvant paclitaxel and carboplatin (PC) chemotherapy. There is no standard first line chemotherapy at disease recurrence. Data extrapolated from ovarian cancer has suggested that patients with recurrent EC may benefit from further platinum-based chemotherapy. We performed a retrospective analysis of patients who were retreated with PC chemotherapy for recurrent EC at Memorial Sloan Kettering Cancer Center between January 2000 and December 2014. The median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Twenty patients were included in the analysis. Patients were re-treated with PC a median of 25 (8-79) months from their original PC. There were no complete responses, 10 (50%) patients had partial response (PR), 3 (15%) had stable disease, 2 (10%) had progression at best response and 5 (20%) were not evaluable by RECIST. A median of 6 cycles of PC were administered (2-9). Four patients (20%) transitioned to paclitaxel only due to carboplatin allergy. At the data cut off, one patient continued PC, and another was off therapy with PR. The remainder ( = 18, 90%) received a median of 2.5 (1-6) further lines of treatments. Median PFS and OS from re-treatment were 10 and 27 months respectively. Median OS from original diagnosis was 74 months. In this small retrospective study, selected patients with recurrent EC who are >6 months from completion of PC derive benefit from retreatment with PC with a response rate of 50%.
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http://dx.doi.org/10.1016/j.gore.2019.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461565PMC
May 2019

Correction: Toward automation of germline variant curation in clinical cancer genetics.

Genet Med 2019 Jul;21(7):1668

Niehaus Center For Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

An update to the original published conflict of interest for author Liying Zhang, PhD. L.Z. received compensation from Future Technology Research LLC (seminar on precision medicine), Roche Diagnostics Asia Pacific, BGI, Illumina (speaking activities at conferences/workshop). L.Z.'s family member has a leadership position and ownership interest of Shanghai Genome Center. This correction has been made.
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http://dx.doi.org/10.1038/s41436-019-0490-5DOI Listing
July 2019
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