Publications by authors named "Joanne Chou"

133 Publications

Pancreatic cancer stem cells may define tumor stroma characteristics and recurrence patterns in pancreatic ductal adenocarcinoma.

BMC Cancer 2021 Apr 9;21(1):385. Epub 2021 Apr 9.

Memorial Sloan Kettering Cancer Center, 300 East 66th street, office 1021, New York, NY, 10065, USA.

Background: Herein, we investigate the relationship between pancreatic stem cell markers (PCSC markers), CD44, and epithelial-specific antigen (ESA), tumor stroma, and the impact on recurrence outcomes in pancreatic ductal adenocarcinoma (PDAC) patients.

Methods: PDAC patients who underwent surgical resection between 01/2012-06/2014 were identified. CD44 and ESA expression was assessed by immunohistochemistry. Stroma was classified as loose, moderate, and dense based on fibroblast content. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier method and compared between subgroups by log-rank test. The association between PCSC markers and stroma type was assessed by Fisher's exact test.

Results: N = 93 PDAC patients were identified. The number of PDAC patients with dense, moderate density, and loose stroma was 11 (12%), 51 (54%), and 31 (33%) respectively. PDAC with CD44/ESA had highest rate of loose stroma (63%) followed by PDAC CD44/ESA (50%), PDAC CD44ESA (35%), CD44ESA (9%) (p = 0.0033). Conversely, lack of CD44 and ESA expression was associated with the highest rate of moderate and dense stroma (91% p = 0.0033). No local recurrence was observed in patients with dense stroma and 9 had distant recurrence. The highest rate of cumulative local recurrence was observed in patients with loose stroma. No statistically significant difference in RFS and OS was observed among subgroups (P = 0.089).

Conclusions: These data indicate PCSCs may have an important role in stroma differentiation in PDAC. Our results further suggest that tumor stroma may influence the recurrence pattern in PDAC patients.
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http://dx.doi.org/10.1186/s12885-021-08123-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034174PMC
April 2021

Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes.

J Natl Cancer Inst 2021 Mar 23. Epub 2021 Mar 23.

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

Background: Recent evidence suggests a rising incidence of cancer in younger individuals. Herein, we report the epidemiologic, pathologic, and molecular characteristics of a patient cohort with early-onset pancreas cancer (EOPC).

Methods: Institutional databases were queried for demographics, treatment history, genomic results and outcomes. Overall survival (OS) from date of diagnosis was estimated using Kaplan-Meier method.

Results: Four hundred and fifty patients with EOPC were identified at Memorial Sloan Kettering between 2008 and 2018. Median OS was 16.3 months (95% confidence interval [CI] = 14.6 to 17.7 months) in the entire cohort and 11.3 months (95% CI = 10.2 to 12.2 months) for patients with stage IV disease at diagnosis. One hundred and thirty-two (29.3% of the cohort) underwent somatic testing; 21 of 132 (15.9%) had RAS wild-type cancers with identification of several actionable alterations, including ETV6-NTRK3, TPR-NTRK1, SCLA5-NRG1 and ATP1B1-NRG1 fusions, IDH1 R132C mutation, and mismatch repair deficiency. One hundred and thirty-eight (30.7% of the cohort) underwent germline testing; 44 of 138 (31.9%) had a pathogenic germline variant (PGV) and 27.5% harbored alterations in cancer susceptibility genes. Of patients seen between 2015 and 2018, 30 of 193 (15.5%) had a pathogenic germline variant. Among 138 who underwent germline testing, those with a PGV had a reduced all-cause mortality compared to patients without a PGV controlling for stage and year of diagnosis (hazard ratio = 0.42, 95%CI = 0.26 to 0.69).

Conclusions: PGVs are present in a substantial minority of patients with EOPC. Actionable somatic alterations were identified frequently in EOPC, enriched in the RAS wild-type subgroup. These observations underpin the recent guidelines for universal germline testing and somatic profiling in pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.1093/jnci/djab038DOI Listing
March 2021

Prophylactic Lateral Neck Dissection for Medullary Thyroid Carcinoma is not Associated with Improved Survival.

Ann Surg Oncol 2021 Mar 21. Epub 2021 Mar 21.

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

Background: Patients with medullary thyroid carcinoma (MTC) often receive lateral lymph node dissection with total thyroidectomy when calcitonin levels are elevated, even in the absence of structural disease, but the effect of this intervention on disease-specific outcomes is not known.

Patients And Methods: We retrospectively reviewed patients from 1986 to 2017 who underwent thyroidectomy with curative intent for MTC at our institution. The association of disease-specific survival and clinicopathologic features was examined using univariate and multivariate Cox regression.

Results: We identified 316 patients who underwent curative resection for MTC. Overall and disease-specific survival were 76% and 86%, respectively, at 10 years. To investigate the effect of prophylactic ipsilateral lateral lymph node dissection, we analyzed 89 patients without known structural disease in the neck lymph nodes at the time of resection and preoperative calcitonin > 200 pg/ml, of whom 45 had an ipsilateral lateral lymph node dissection (LND) and 44 did not. There were no differences in tumor size or preoperative calcitonin levels. There was no difference at 10 years in cumulative incidence of recurrence in the neck (20.9% LND vs. 30.4% no LND, p = 0.46), cumulative incidence of distant recurrence (18.3% vs. 18.4%, p = 0.97), disease-specific survival (86% vs. 93%, p = 0.53), or overall survival (82% vs. 90%, p = 0.6).

Conclusion: Lateral neck dissection in the absence of clinical or radiologic abnormal lymph nodes is not associated with improved survival in patients with MTC.
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http://dx.doi.org/10.1245/s10434-021-09683-8DOI Listing
March 2021

Ribociclib and everolimus in well-differentiated foregut neuroendocrine tumors.

Endocr Relat Cancer 2021 Apr;28(4):237-246

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

The mammalian target of rapamycin inhibitor everolimus is an established therapy for well-differentiated (WD) foregut neuroendocrine tumors (NETs). Pre-clinical data demonstrates a potential synergistic role for cyclin dependent kinase 4/6 inhibition and everolimus to treat this disease. In this phase II multicenter study, patients with advanced foregut WDNETs received combination ribociclib and everolimus until confirmed disease progression or unacceptable toxicity. The first 12 patients received ribociclib 300 mg three weeks in a row with a 1 week break and everolimus 2.5 mg daily (recommended phase II dose). Due to unexpected hematologic and infectious toxicities, the trial was put on hold, modified, and an additional 9 patients received ribociclib 200 mg and everolimus 2.5 mg daily. The primary end point was progression-free survival. Archived pre-treatment tumor was profiled by next-generation sequencing to evaluate for genomic markers of drug response. Twenty-one patients were treated (median age, 56; range, 24 to 77). The study did not meet the pre-specified criteria to advance to stage two. No patients experienced an objective response. Thirteen patients (62%) experienced stable disease. Median progression-free survival was 7.7 months (95% CI, 2.8 months to not reached). Eleven of the first 12 patients (92%) developed grade 2 or more myelosuppression. Ten patients (84%) experienced treatment interruption and 8 patients (67%) required dose reduction. Genetic testing in archival tumor tissue samples failed to identify a predictive biomarker of disease stabilization. The combination of ribociclib and everolimus had insufficient activity to warrant further investigation in foregut WDNETs.
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http://dx.doi.org/10.1530/ERC-20-0446DOI Listing
April 2021

Platinum-Based Treatment for Well- and Poorly Differentiated Pancreatic Neuroendocrine Neoplasms.

Pancreas 2021 Feb;50(2):138-146

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

Objectives: Pancreatic neuroendocrine neoplasms include well-differentiated tumors (PanNETs) and poorly differentiated carcinomas (PanNECs). Previous reports suggested a role for platinum-based therapy largely in PanNEC. We sought to investigate the role of platinum-based therapy in pancreatic neuroendocrine neoplasms regardless of tumor grade and differentiation.

Methods: Patients with pancreatic neuroendocrine neoplasms treated with platinum-based therapy at Memorial Sloan Kettering (1994-2016) and Verona University Hospital (2008-2016) were retrospectively identified. Response to treatment by RECIST v1.1, overall survival, and progression-free survival were defined. Among patients with available tissue, DAXX, ATRX, Rb, and p53 expression was evaluated to support the histologic grade of differentiation.

Results: Fifty PanNETs, 29 PanNECs, and 22 high-grade tumors with undeterminable differentiation were included. No patients achieved complete response. Overall rate of partial response was 31%, 41% for PanNEC, and 20% for PanNETs. Among PanNETs, partial response was achieved in 33% of G1 (2/6), 10% of G2 (2/19), and 24% of G3 (6/25) tumors. Median overall survival was 29.3 months for PanNETs and 10.9 months for PanNEC (P < 0.001). There was no significant difference in median progression-free survival (P = 0.2).

Conclusions: Platinum-based therapies demonstrated increased activity in PanNEC; however, promising efficacy was also observed in PanNETs, irrespective of grade.
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http://dx.doi.org/10.1097/MPA.0000000000001740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880539PMC
February 2021

Change in Neutrophil-to-Lymphocyte Ratio During Neoadjuvant Treatment Does Not Predict Pathological Response and Survival in Resectable Pancreatic Ductal Adenocarcinoma.

Am Surg 2021 Jan 31:3134821989050. Epub 2021 Jan 31.

Department of Surgery, 5803Memorial Sloan Kettering Cancer Center, NY, USA.

Background: Neutrophil-to-lymphocyte ratio (NLR) has been reported as prognostic in pancreatic ductal adenocarcinoma (PDAC). Data about NLR changes during neoadjuvant therapy (NAT) and its relationship with pathological tumor response and survival are lacking.

Methods: Pancreatic ductal adenocarcinoma patients with NAT followed by resection between 2009 and 2015 were identified from a prospective database. Neutrophil-to-lymphocyte ratio was collected prior to NAT (baseline), on chemotherapy (prior to cycle 3), and prior to surgery. Baseline NLR, and changes in NLR between baseline and on chemotherapy (delta 1) and between baseline and surgery (delta 2) were compared with pathologic response (<90% and ≥90% defined as poor and good), overall (OS), and disease-free survival (DFS) using Wilcoxon rank-sum and Cox proportional hazard models.

Results: Of 93 patients, 17% had good pathological response. Median (interquartile range) NLR at baseline, third cycle, and surgery were 2.7 (2.0-3.7), 2.5 (1.9-4.1), and 3.1 (2.1-5.3), respectively. Median change in NLR from baseline to third cycle was .06 ( = .72), and .6 from baseline to surgery ( < .01). Baseline NLR, delta 1, and delta 2 were not associated with pathological response, OS, or DFS.

Discussion: Neutrophil-to-lymphocyte ratio increased after NAT, but a significant association between NLR and pathological response, OS, and DFS in resected PDAC patients was not observed.
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http://dx.doi.org/10.1177/0003134821989050DOI Listing
January 2021

Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair-proficient Metastatic Colorectal Cancer.

Clin Cancer Res 2021 Apr 27;27(8):2200-2208. Epub 2021 Jan 27.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.

Patients And Methods: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.

Results: We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9-26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0-27.0]. The median progression-free survival was 1.8 (95% CI, 1.7-1.9) months, median overall survival was 11.4 (95% CI, 10.1-17.4) months. Twenty five percent of patients ( = 6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8 T lymphocyte activation, differentiation, and proliferation in patients with objective response.

Conclusions: This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2474DOI Listing
April 2021

General cancer screening practices among adult survivors of retinoblastoma: Results from the Retinoblastoma Survivor Study.

Pediatr Blood Cancer 2021 Apr 26;68(4):e28873. Epub 2021 Jan 26.

Department of Epidemiology and Biostatistics, MSKCC, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

We assessed breast, cervical, and colorectal cancer screening practices in adult retinoblastoma (Rb) survivors and non-Rb controls. We found that most Rb survivors adhered to general population cancer screening recommendations. Rates did not differ among Rb survivors and non-Rb controls, or among survivors by laterality, even though bilateral survivors reported higher levels of concern about future health and cancer risk. Older age, being overweight/obese, and lack of recent contact with medical personnel were independently associated with decreased utilization of Pap smear among female Rb survivors. Future studies are warranted to determine whether these associations might provide an opportunity for intervention.
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http://dx.doi.org/10.1002/pbc.28873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904654PMC
April 2021

Differences in Liver Parenchyma are Measurable with CT Radiomics at Initial Colon Resection in Patients that Develop Hepatic Metastases from Stage II/III Colon Cancer.

Ann Surg Oncol 2021 Apr 20;28(4):1982-1989. Epub 2020 Sep 20.

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

Background: Currently, there are no methods to identify patients with an increased risk of liver metastases to guide patient selection for liver-directed therapies. We tried to determine whether quantitative image features (radiomics) of the liver obtained from preoperative staging CT scans at the time of initial colon resection differ in patients that subsequently develop liver metastases, extrahepatic metastases, or demonstrate prolonged disease-free survival.

Methods: Patients who underwent resection of stage II/III colon cancer from 2004 to 2012 with available preoperative CT scans were included in this single-institution, retrospective case-control study. Patients were grouped by initial recurrence patterns: liver recurrence, extrahepatic recurrence, or no evidence of disease at 5 years. Radiomic features of the liver parenchyma extracted from CT images were compared across groups.

Results: The cohort consisted of 120 patients divided evenly between three recurrence groups, with an equal number of stage II and III patients in each group. After adjusting for multiple comparisons, 44 of 254 (17%) imaging features displayed different distributions across the three patient groups (p < 0.05), with the clearest distinction between those with liver recurrence and no evidence of disease. Increased heterogeneity in the liver parenchyma by radiomic analysis was protective of liver metastases.

Conclusions: CT radiomics is a promising tool to identify patients at high risk of developing liver metastases and is worthy of further investigation and validation.
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http://dx.doi.org/10.1245/s10434-020-09134-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940539PMC
April 2021

Early liver metastases after "failure" of adjuvant chemotherapy for stage III colorectal cancer: is there a role for additional adjuvant therapy?

HPB (Oxford) 2021 Apr 14;23(4):601-608. Epub 2020 Sep 14.

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

Background: The utility of adjuvant chemotherapy after resection of colorectal liver metastasis (CLM) in patients with rapid recurrence after adjuvant chemotherapy for their primary tumor is unclear. The aim of this study was to evaluate the oncologic benefit of adjuvant hepatic arterial plus systemic chemotherapy (HAIC + Sys) in patients with early CLM.

Methods: A retrospective analysis of patients with early CLM (≤12 months of adjuvant chemotherapy for primary tumor) who received either HAIC + Sys, adjuvant systemic chemotherapy alone (Sys), or active surveillance (Surgery alone) following resection of CLM was performed. Recurrence and survival were compared between treatment groups using Kaplan-Meier methods and Cox proportional hazards models.

Results: Of 239 patients undergoing resection of early CLM, 79 (33.1%) received HAIC + Sys, 77 (32.2%) received Sys, and 83 (34.7%) had Surgery alone. HAIC + Sys was independently associated with reduced risk of RFS events (adjusted hazard ratio [HRadj]: 0.64, 95%CI:0.44-0.94, p = 0.022) and all-cause mortality (HRadj: 0.54, 95%CI:0.36-0.81, p = 0.003) compared to Surgery alone patients. Largest tumor >5 cm (HRadj: 2.03, 95%CI: 1.41-2.93, p < 0.001) and right-sided colon tumors (HRadj: 1.93, 95%CI: 1.29-2.89, p = 0.002) were independently associated with worse OS.

Conclusion: Adjuvant HAIC + Sys after resection of early CLM that occur after chemotherapy for node-positive primary is associated with improved outcomes.
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http://dx.doi.org/10.1016/j.hpb.2020.08.018DOI Listing
April 2021

Predicting malignancy in patients with adrenal tumors using F-FDG-PET/CT SUVmax.

J Surg Oncol 2020 Dec 10;122(8):1821-1826. Epub 2020 Sep 10.

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

Background And Objectives: F-fluorodeoxyglucose positron emission tomography/computed tomography ( F-FDG-PET/CT) parameters may help distinguish malignant from benign adrenal tumors, but few have been externally validated or determined based on definitive pathological confirmation. We determined and validated a threshold for F-FDG-PET/CT maximum standard uptake value (SUVmax) in patients who underwent adrenalectomy for a nonfunctional tumor.

Methods: Database review identified patients with F-FDG-PET/CT images available (training cohort), or only SUVmax values (validation cohort). Discriminative accuracy was assessed by area under the curve (AUC), and the optimal cutoff value estimated by maximally selected Wilcoxon rank statistics.

Results: Of identified patients (n = 171), 86 had adrenal metastases, 20 adrenal cortical carcinoma, and 27 adrenal cortical adenoma. In the training cohort (n = 96), SUVmax was significantly higher in malignant versus benign tumors (median 8.3 vs. 3.0, p < .001), with an AUC of 0.857. Tumor size did not differ. The optimal cutoff SUVmax was 4.6 (p < .01). In the validation cohort (n = 75), this cutoff had a sensitivity of 75% and specificity 55%.

Conclusions: F-FDG-PET/CT SUVmax was associated with malignancy. Validation indicated that SUVmax ≥ 4.6 was suggestive of malignancy, while lower values did not reliably predict benign tumor.
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http://dx.doi.org/10.1002/jso.26203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793554PMC
December 2020

Phase II trial of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma after disease progression on sorafenib.

Cancer Med 2020 10 25;9(20):7453-7459. Epub 2020 Aug 25.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Patients with advanced hepatocellular carcinoma (HCC) who received second line sorafenib plus doxorubicin following disease progression on sorafenib were shown retrospectively to have improved progression free survival (PFS) and overall survival (OS). Sorafenib plus doxorubicin combination may synergistically promote ASK-1 mediated apoptosis in cancer cells through RAF-1 inhibition. Thus, we conducted this phase II study of sorafenib and doxorubicin combination following progression on sorafenib.

Methods: Patients with histologically confirmed advanced HCC, confirmed radiologic progression on sorafenib, Karnofsky performance status (KPS) ≥70%, and Child-Pugh A liver cirrhosis were eligible. Patients received sorafenib 400 mg twice daily and doxorubicin 60 mg/m once every 3-weeks. The primary endpoint was OS at 6 months (OS6). Secondary endpoints included safety, PFS, OS, response rate (RR) by RECIST 1.1. Additional endpoints included baseline and on-treatment tumor ASK-1 and pERK expression levels by immunohistochemistry (IHC) and the correlation with PFS, RR, and OS.

Results: Thirty patients were enrolled in the study, 86% were male, median age was 64 years. OS6 was 76.6% (95%CI: 57.2%-88.1%). Median OS was 8.6 (95%CI: 7.3-12) months, and median PFS reached 3.9 (95%CI: 2.4-4.6) months. Three (11%) partial responses were observed and 17 patients (61%) had stable disease. Pertinent grade 3-4 adverse events that occurred in more than 10% of patients included neutropenia (16%), febrile neutropenia (10%), anemia (10%), thrombocytopenia (10%), elevated AST (23%) and ALT (10%), hypophosphatemia (10%), and fatigue (10%). No association with the difference in baseline and post-treatment ASK-1 and pERK level of expression by IHC and survival outcomes was detected.

Conclusion: Sorafenib plus doxorubicin following progression on sorafenib did not show any improved outcome. We do not recommend further development or use of this combination in HCC.
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http://dx.doi.org/10.1002/cam4.3389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571806PMC
October 2020

Systemic Chemotherapy for Metastatic Colitis-Associated Cancer Has a Worse Outcome Than Sporadic Colorectal Cancer: Matched Case Cohort Analysis.

Clin Colorectal Cancer 2020 Dec 8;19(4):e151-e156. Epub 2020 Feb 8.

Department of Medicine. Electronic address:

Background: Colitis-associated cancers (CAC) are a catastrophic complication of inflammatory bowel disease; at diagnosis, CAC is frequently at an advanced stage. Although the genomic alterations (GA) in CAC are different from sporadic colorectal cancer (CRC), the same systemic therapies are used. We compared clinically relevant outcomes using standard care systemic chemotherapy of stage IV CAC versus a matched patient control cohort of stage IV CRC patients.

Patients And Methods: A retrospective matched cohort design was used. Eighteen cases of stage IV CAC (7 ulcerative colitis, 11 Crohn disease) and 18 CRC were identified. GA analysis was available for all patients. Outcome endpoints included response rate and response duration, progression-free survival, and OS.

Results: Although the response rates were similar (CAC 35.7% vs. CRC 57.1%, P = .45), the median duration of response for CAC was significantly shorter (1.4 months, vs. CRC 11.8 months, P = .006). There was no difference in dose density of first-line therapy between cohorts, suggesting that shorter response duration was due to more rapid development of chemotherapy resistance. Median OS was significantly shorter for CAC patients (13 vs. 27.6 months, P = .034). As expected, there was a difference in the spectrum of GA between CAC and CRC cohorts. However, GA associated with poor prognosis (eg, B-Raf) were no more frequent in the CAC cohort.

Conclusion: Clinically meaningful outcomes of duration of response and OS are worse for CAC versus sporadic CRC patients treated with FOLFOX or FOLFIRI as first therapy for metastatic disease.
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http://dx.doi.org/10.1016/j.clcc.2020.02.008DOI Listing
December 2020

Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver.

Cancer 2020 Sep 14;126(18):4126-4135. Epub 2020 Jul 14.

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

Background: Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in-frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets.

Methods: Archival fresh, formalin-fixed, paraffin-embedded samples from patients with FLC who prospectively consented to an institutional review board-approved protocol were analyzed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a next-generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA-Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations.

Results: A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1-PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK-IMPACT did not detect the fusion, its presence was confirmed by targeted RNA-Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6-153 months). The 3-year overall survival rate was 84% (95% CI, 61%-93%).

Conclusions: The DNAJB1-PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1-PRKACA fusion transcript or any therapeutic target identified from next-generation sequencing in patients with FLC.
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http://dx.doi.org/10.1002/cncr.32960DOI Listing
September 2020

Hepatocellular carcinoma in patients with no identifiable risk factors.

HPB (Oxford) 2021 Jan 24;23(1):118-126. Epub 2020 Jun 24.

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

Background: A subset of patients have no risk factors for the development of hepatocellular carcinoma (HCC). We evaluated differences in clinical variables between patients with and without risk factors who underwent surgical resection.

Methods: A prospectively maintained database was queried for patients who underwent R0/R1 resection of HCC between 1992 and 2016. Risk factors included HCV, HBV, hemochromatosis, alcoholic liver disease, or cirrhosis, stage 2 or 3 fibrosis or severe (>66%) steatosis of the non-neoplastic liver. Variables were compared between patients with and without risk factors.

Results: There were 416 patients who underwent resection; 276 (66%) had known risk factors while 140 (34%) did not. Patients without risk factors were more likely to be older, female and have hyperlipidemia or coronary artery disease (p < 0.004). These patients had larger tumors and were more likely to undergo major hepatectomy (p < 0.001). There was no difference in OS (5-year, 56% vs 47%, p = 0.335), RFS (27% vs 24%, p = 0.398), or the rates of intrahepatic (HR:1.16 [95%CI:0.95-1.57], p = 0.344) and extrahepatic recurrences (HR:0.72 [95%CI:0.4-1.3], p = 0.261) between groups.

Conclusion: Patients without risk factors for HCC presented with larger tumors yet had similar outcomes, suggesting these tumors may represent a different disease process, and underlying liver dysfunction can influence overall outcome.
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http://dx.doi.org/10.1016/j.hpb.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022289PMC
January 2021

Alterations in driver genes are predictive of survival in patients with resected pancreatic ductal adenocarcinoma.

Cancer 2020 Sep 23;126(17):3939-3949. Epub 2020 Jun 23.

Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection.

Methods: Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genomic alterations were determined on the basis of MSK-IMPACT results from formalin-fixed, paraffin-embedded samples. Associations between genomic alterations and clinical outcomes were assessed.

Results: Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow-up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0-45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P = .043; median for TP53, 37.4 months [95% CI, 32.1-42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P = .035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3-45.5 months] vs 39.2 months [95% CI, 37.4-75.2 months]; P = .012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4-75.2 months] vs 33.9 months [95% CI, 24.0-39.0 months]; P = .020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6-44.2 months] vs 39.2 months [95% CI, 34.5-49.1 months]; P = .048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01-2.33; P = .042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0-49.8 months; P = .035).

Conclusions: In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC.
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http://dx.doi.org/10.1002/cncr.33038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424538PMC
September 2020

Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

Oncologist 2020 12 2;25(12):e1825-e1836. Epub 2020 Jul 2.

Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA.

Lessons Learned: Androgen receptor as assessed by immunohistochemistry is expressed in a high proportion of patients with hepatocellular carcinoma (HCC). Enzalutamide at 160 mg orally daily is safe and tolerable in patients with advanced HCC but has no single-agent antitumor activity. Enzalutamide, a CYP3A4 inducer, at a standard dose of 160 mg reduces the exposure of sorafenib, a CYP3A4 substrate. Enzalutamide and sorafenib is safe and tolerable in patients with advanced HCC, but the addition of enzalutamide to sorafenib did not enhance the antitumor activity of sorafenib.

Background: Androgen receptor (AR) interference is deleterious to hepatocellular carcinoma (HCC) in preclinical models.

Methods: This is a multicenter, phase Ib study of enzalutamide ± sorafenib in patients with advanced HCC. In part 1, a 3 + 3 dose de-escalation design with expansion established the recommended phase II dose (RP2D) of enzalutamide in patients in whom sorafenib treatment had failed. In part 2, a 3 + 3 dose escalation with expansion established the safety of enzalutamide with sorafenib in treatment-naive patients with HCC. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and determination of AR expression by immunohistochemistry. A 7-day run-in with sorafenib alone in part 2 allowed assessment of the impact of enzalutamide on sorafenib pharmacokinetics.

Results: In part 1, 16 patients received enzalutamide 160 mg daily. No dose-limiting toxicity (DLT) occurred; 1 patient required dose reduction. Responses were not observed; median PFS and OS were 1.8 (95% confidence interval [CI]: 1.6-3.6) and 7 (95% CI: 3.6 to not reached [NR]) months, respectively. In part 2, patients received sorafenib 400 mg daily (4) or twice a day (8) both with enzalutamide at the recommended phase II dose-no DLTs were observed. ORR was 10% (95% CI: 0.3-44.5), and median PFS and OS were 2.9 (95% CI: 1.6 to NR) and 6.7 (95% CI: 4.6 to NR) months, respectively. Enzalutamide reduced sorafenib exposure by 60%. Tumor AR expression did not associate with outcome.

Conclusion: Enzalutamide is ineffective in HCC; further development is not supported by this study.
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http://dx.doi.org/10.1634/theoncologist.2020-0521DOI Listing
December 2020

Detailed Analysis of Margin Positivity and the Site of Local Recurrence After Pancreaticoduodenectomy.

Ann Surg Oncol 2021 Jan 25;28(1):539-549. Epub 2020 May 25.

Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering, New York, NY, USA.

Background: The association between a positive surgical margin and local recurrence after resection of pancreatic adenocarcinoma (PDAC) has been reported. Assessment of the location of the a positive margin and the specific site of local recurrence has not been well described.

Methods: A prospectively maintained database was queried for patients who underwent R0/R1 pancreaticoduodenectomy for PDAC between 2000 and 2015. The pancreatic, posterior, gastric/duodenal, anterior peritoneal, and bile duct margins were routinely assessed. Postoperative imaging was reviewed for the site of first recurrence, and local recurrence was defined as recurrence located in the remnant pancreas, surgical bed, or retroperitoneal site outside the surgical bed.

Results: During the study period, 891 patients underwent pancreaticoduodenectomy, and 390 patients had an initial local recurrence with or without distant metastases. The 5-year cumulative incidence of local recurrence by site included the remnant pancreas (4%; 95% confidence interval [CI], 3-5%), the surgical bed (35%; 95% CI, 32-39%), and other regional retroperitoneal site (4%; 95% CI, 3-6%). In the univariate analysis, positive posterior margin (hazard ratio [HR], 1.50; 95% CI, 1.17-1.91; p = 0.001) and positive lymph nodes (HR, 1.36; 95% CI, 1.06-1.75; p = 0.017) were associated with surgical bed recurrence, and in the multivariate analysis, positive posterior margin remained significant (HR, 1.40; 95% CI, 1.09-1.81; p = 0.009). An isolated local recurrence was found in 197 patients, and a positive posterior margin was associated with surgical bed recurrence in this subgroup (HR, 1.51; 95% CI, 1.08-2.10; p = 0.016).

Conclusion: In this study, the primary association between site of margin positivity and site of local recurrence was between the posterior margin and surgical bed recurrence. Given this association and the limited ability to modify this margin intraoperatively, preoperative assessment should be emphasized.
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http://dx.doi.org/10.1245/s10434-020-08600-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918294PMC
January 2021

Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection.

Clin Cancer Res 2020 07 22;26(13):3239-3247. Epub 2020 May 22.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.

Experimental Design: We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: , and HRm status was grouped as: (i) germline versus somatic; (ii) core ( and versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden.

Results: Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median [95% confidence interval (CI)] follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum [HR, 0.44 (95% CI: 0.29-0.67); < 0.01], but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum.

Conclusions: Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380542PMC
July 2020

First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial.

Lancet Oncol 2020 06 18;21(6):821-831. Epub 2020 May 18.

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

Background: Addition of trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and activity of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric (gastric, oesophageal, or gastroesophageal junction) cancer.

Methods: This study was an investigator-initiated, open-label, non-randomised, single-arm, single centre, phase 2 trial in patients aged 18 years or older with HER2-positive metastatic oesophagogastric cancer. Eligible patients had measurable or evaluable non-measurable disease, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and left ventricular ejection fraction of at least 53%. Patients were eligible to receive an initial induction cycle of 200 mg flat dose of intravenous pembrolizumab and 8 mg/kg loading dose of intravenous trastuzumab. For subsequent cycles, patients received 130 mg/m of intravenous oxaliplatin or 80 mg/m of cisplatin on day 1, 850 mg/m of oral capecitabine twice a day for 2 weeks followed by 1 week off (or intravenous 5-fluorouracil, 800 mg/m per day on days 1-5), and a 200 mg flat dose of intravenous pembrolizumab, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival, defined as the proportion of patients alive and free of progression at 6 months, assessed in patients who received at least one dose of trastuzumab and pembrolizumab. The regimen would be considered worthy of further investigation if 26 or more of 37 patients were progression-free at 6 months. This trial is registered with ClinicalTrials.gov, NCT02954536, and is ongoing, but closed to enrolment.

Findings: Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, median follow-up among survivors was 13·0 months (IQR 11·7-23·5). The primary endpoint was achieved; 26 (70%; 95% CI 54-83) of 37 patients were progression-free at 6 months. The most common treatment-related adverse event of any grade was neuropathy, which was reported in 36 (97%) of 37 patients. The most common grade 3 or 4 adverse events were lymphocytopenia (seven [19%] patients with grade 3 and two [5%] with grade 4), grade 3 decreased electrolytes (six [16%] patients), and grade 3 anaemia (four [11%] patients). Serious adverse events occurred in two patients patients (both grade 3 nephritis leading to treatment discontinuation). Four patients discontinued pembrolizumab because of immune-related adverse events. There were no treatment-related deaths.

Interpretation: Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomised phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric cancer is underway.

Funding: Merck & Co.
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http://dx.doi.org/10.1016/S1470-2045(20)30169-8DOI Listing
June 2020

A Multicenter Randomized Three-Arm Phase II Study of (1) Everolimus, (2) Estrogen Deprivation Therapy (EDT) with Leuprolide + Letrozole, and (3) Everolimus + EDT in Patients with Unresectable Fibrolamellar Carcinoma.

Oncologist 2020 11 26;25(11):925-e1603. Epub 2020 May 26.

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

Lessons Learned: FLC is a complex cancer with many implicated oncogenic pathways. Single or dual targeting does not appear to alter the natural history of the cancer, and novel therapeutics are needed. Estrogen deprivation therapy with letrozole and leuprolide, alone or in combination with the mTOR inhibitor, everolimus, did not demonstrate clinical activity in advanced fibrolamellar carcinoma. The study drugs were well tolerated when administered as single agents or in combination in this patient population. This study demonstrates that, despite the rarity of FLC, multicenter therapeutic clinical trials are feasible and support the value of this consortium.

Background: Fibrolamellar carcinoma (FLC) is an uncommon malignancy in young people and is sometimes associated with pregnancy and oral contraceptive use. Immunohistochemical staining and genetic profiling of FLC tumor specimens have revealed aromatase overexpression. The overexpression of mTOR and S6 kinase has been noted in 25% of FLC. On the basis of interaction between estrogen and the PI3K/Akt/mTOR pathway, we hypothesized that suppression of estrogen and mTOR signaling could have antineoplastic activity in FLC.

Methods: Patients were randomized to arm A (everolimus), arm B (letrozole/leuprolide; estrogen deprivation therapy [EDT]), or arm C (everolimus/letrozole/leuprolide). Upon disease progression, patients in arm A or B could proceed to part 2 (everolimus/letrozole/leuprolide). The primary endpoint was progression-free survival (PFS) at 6 months (PFS6) assessed using a Simon's minimax two-stage design, hypothesizing an improvement in PFS6 from 40% to 64% with the study regimen.

Results: Twenty-eight patients were enrolled. An unplanned analysis was performed because of perceived concern for lack of efficacy. Stable disease was observed in 9 of 26 evaluable patients (35%). PFS6 was 0%. Median overall survival (OS) was 12.4 months (95% confidence interval [CI], 7.4-20.9) for the whole study cohort. Grade 3 adverse events in ≥10% of patients were nausea (11%), vomiting (11%), anemia (11%), elevated aspartate transaminase (AST; 32%), alanine transaminase (ALT; 36%), and alkaline phosphatase (14%). All 28 patients experienced an event for PFS outcome, and four deaths were due to disease progression.

Conclusion: Neither EDT nor mTOR inhibition improved outcomes in FLC. Other treatment strategies are needed.
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http://dx.doi.org/10.1634/theoncologist.2020-0367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648371PMC
November 2020

Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline Mutation.

J Clin Oncol 2020 05 24;38(13):1378-1388. Epub 2020 Jan 24.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline or (g+) mutation. Phase IB data from a trial that used cisplatin, gemcitabine, and veliparib treatment demonstrated a high response rate (RR), disease control rate (DCR), and overall survival (OS) in this population. We designed an open-label, randomized, multicenter, two-arm phase II trial to investigate cisplatin and gemcitabine with or without veliparib in g+ PDAC.

Patients And Methods: Eligible patients had untreated g PDAC with measurable stage III to IV disease and Eastern Cooperative Oncology Group performance status of 0 to 1. Treatment for patients in arm A consisted of cisplatin 25 mg/m and gemcitabine 600 mg/m intravenously on days 3 and 10; treatment for patients in arm B was the same as that for patients in arm A, and arm A also received veliparib 80 mg orally twice per day on days 1 to 12 cycled every 3 weeks. The primary end point was RRs of arm A and arm B evaluated separately using a Simon two-stage design. Secondary end points were progression-free survival, DCR, OS, safety, and correlative analyses.

Results: Fifty patients were evaluated by modified intention-to-treat analysis. The RR for arm A was 74.1% and 65.2% for arm B ( = .55); both arms exceeded the prespecified activity threshold. DCR was 100% for arm A and 78.3% for arm B ( = .02). Median progression-free survival was 10.1 months for arm A (95% CI, 6.7 to 11.5 months) and 9.7 months for arm B (95% CI, 4.2 to 13.6 months; = .73). Median OS for arm A was 15.5 months (95% CI, 12.2 to 24.3 months) and 16.4 months for arm B (95% CI, 11.7 to 23.4 months; = .6). Two-year OS rate for the entire cohort was 30.6% (95% CI, 17.8% to 44.4%), and 3-year OS rate was 17.8% (95% CI, 8.1% to 30.7%). Grade 3 to 4 hematologic toxicities for arm A versus arm B were 13 (48%) versus seven (30%) for neutropenia, 15 (55%) versus two (9%) for thrombocytopenia, and 14 (52%) versus eight (35%) for anemia.

Conclusion: Cisplatin and gemcitabine is an effective regimen in advanced g+ PDAC. Concurrent veliparib did not improve RR. These data establish cisplatin and gemcitabine as a standard approach in g/+ PDAC.
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http://dx.doi.org/10.1200/JCO.19.02931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193749PMC
May 2020

Impact of enucleation on adult retinoblastoma survivors' quality of life: A qualitative study of survivors' perspectives.

Palliat Support Care 2020 06;18(3):322-331

Memorial Sloan Kettering Cancer Center, New York, NY.

Objectives: Retinoblastoma is the most common primary intraocular tumor of childhood with >95% survival rates in the US. Traditional therapy for retinoblastoma often included enucleation (removal of the eye). While much is known about the visual, physical, and cognitive ramifications of enucleation, data are lacking about survivors' perception of how this treatment impacts overall quality of life.

Methods: Qualitative analysis of an open-ended response describing how much the removal of an eye had affected retinoblastoma survivors' lives and in what ways in free text, narrative form.

Results: Four hundred and four retinoblastoma survivors who had undergone enucleation (bilateral disease = 214; 52% female; mean age = 44, SD = 11) completed the survey. Survivors reported physical problems (n = 205, 50.7%), intrapersonal problems (n = 77, 19.1%), social and relational problems (n = 98, 24.3%), and affective problems (n = 34, 8.4%) at a mean of 42 years after diagnosis. Three key themes emerged from survivors' responses; specifically, they (1) continue to report physical and intrapersonal struggles with appearance and related self-consciousness due to appearance; (2) have multiple social and relational problems, with teasing and bullying being prominent problems; and (3) reported utilization of active coping strategies, including developing more acceptance and learning compensatory skills around activities of daily living.

Significance Of Results: This study suggests that adult retinoblastoma survivors treated with enucleation continue to struggle with a unique set of psychosocial problems. Future interventions can be designed to teach survivors more active coping skills (e.g., for appearance-related issues, vision-related issues, and teasing/bullying) to optimize survivors' long-term quality of life.
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http://dx.doi.org/10.1017/S1478951519000920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205583PMC
June 2020

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

JAMA Oncol 2019 Oct 31. Epub 2019 Oct 31.

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

Importance: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients.

Objective: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC.

Design, Setting, And Participants: A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded.

Interventions: Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin.

Main Outcomes And Measures: The primary outcome was progression-free survival (PFS) of 80% at 6 months.

Results: For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4).

Conclusions And Relevance: Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.
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http://dx.doi.org/10.1001/jamaoncol.2019.3718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824231PMC
October 2019

PD-1 Blockade in Advanced Adrenocortical Carcinoma.

J Clin Oncol 2020 01 23;38(1):71-80. Epub 2019 Oct 23.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC.

Patients And Methods: Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates.

Results: We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response.

Conclusion: MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.
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http://dx.doi.org/10.1200/JCO.19.01586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351334PMC
January 2020

Barriers and facilitators of risk-based health care for adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Cancer 2020 02 18;126(3):619-627. Epub 2019 Oct 18.

Duke University, Durham, North Carolina.

Background: Optimal risk-based survivor health care includes surveillance for late effects and education targeted at reducing or preventing risky health behaviors. Understanding the reasons for a lack of risk-based follow-up care is essential.

Methods: Adult participants from the Childhood Cancer Survivor Study were surveyed about having a cancer-related visit in the past 2 years and the likelihood of having a cancer-related visit in the future. Additional factors thought to be related to the primary outcomes were also assessed.

Results: Nine hundred seventy-five survivors completed the survey. Twenty-seven percent (95% confidence interval [CI], 24%-30%) had a cancer-related medical visit in the previous 2 years, and 41% (95% CI, 38%-44%) planned to have such a visit within the next 2 years. The likelihood of having had a cancer-related visit within the last 2 years was higher among survivors assigning greater importance to these visits (relative risk [RR], 1.2; 95% CI, 1.1-1.3), perceiving greater susceptibility to health problems (RR, 1.2; 95% CI, 1.1-1.3), having a moderate to life-threatening chronic health problem related to their cancer (RR, 2.1; 95% CI, 1.7-2.7), seeing a primary care provider for a cancer-related problem (RR, 1.3; 95% CI, 1.0-1.6), having a cancer treatment summary (RR, 1.3; 95% CI, 1.0-1.6), and endorsing greater confidence in physicians' abilities to address questions and concerns (RR, 1.2; 95% CI, 1.0-1.3).

Conclusions: Educational interventions improving awareness of treatment history and susceptibility to cancer-related late effects and corresponding risk-based care are likely to be beneficial for survivors of childhood cancers.
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http://dx.doi.org/10.1002/cncr.32568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980215PMC
February 2020

Prediction of Recurrence Patterns from Hepatic Parenchymal Disease After Resection of Colorectal Liver Metastases.

Ann Surg Oncol 2020 Jan 15;27(1):188-195. Epub 2019 Oct 15.

Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Obesity and metabolic syndrome are associated with inflammatory hepatic parenchymal disease (HPD) and increased risk for recurrence after resection of colorectal liver metastases (CRLM). The independent impact of HPD on recurrence patterns has not been well defined.

Methods: The nonalcoholic fatty liver disease activity score (NAS) was used to quantify HPD including steatosis and fibrosis for all patients with completely resected CRLM between April 2003 and March 2007. Clinicopathologic factors, perioperative history, and outcomes were compared with the NAS. Fisher's exact test was used to examine the association between severe HPD (NAS ≥ 3) with clinical and perioperative characteristics. Kaplan-Meier methods were used to estimate recurrence-free survival (RFS). The cumulative incidences of recurrence [any intrahepatic recurrence (IHR), extrahepatic recurrence only (EHR), and death without recurrence (DWR)] were estimated using competing risks methods.

Results: Among the 357 patients included in this study, microsteatosis was noted in 124 (35%) patients, severe HPD in 31 (9%), steatohepatitis in 14 (4%), and sinusoidal injury in 36 (10%). After median follow-up of 127 months (range 4-175 months), 10-year RFS was 22% [95% confidence interval (CI) 17-27%]. Ten-year cumulative incidence for IHR, EHR, and DWR was 37%, 30%, and 12%, respectively. After controlling for confounders, NAS ≥ 3 was independently associated with higher risk of IHR [hazard ratio (HR) 1.76, 95% CI 1.07-2.90, p = 0.027] and lower risk of EHR (HR 0.18, 95% CI 0.04-0.75, p = 0.019) on multivariable analysis.

Conclusions: Severe HPD was associated with increased IHR risk and decreased EHR risk. Future investigation into whether improving HPD from reversible etiologies can reduce the risk for IHR is warranted.
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http://dx.doi.org/10.1245/s10434-019-07934-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061284PMC
January 2020

Regorafenib in Combination with First-Line Chemotherapy for Metastatic Esophagogastric Cancer.

Oncologist 2020 01 30;25(1):e68-e74. Epub 2019 Sep 30.

Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USA.

Background: Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer.

Materials And Methods: Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS.

Results: Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single-center phase II study (NCT01913639). The most common grade 3-4 treatment-related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6-month PFS was 53% (95% confidence interval [CI], 38%-71%), the objective response rate was 54% (95% CI, 37%-70%), and the disease control rate was 77% (95% CI, 67%-94%). Next-generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum-based chemotherapy.

Conclusion: Regorafenib (one week on-one week off schedule) is well tolerated in combination with first-line FOLFOX but does not improve 6-month PFS relative to historical control.

Implications For Practice: Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first-line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD-1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.
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http://dx.doi.org/10.1634/theoncologist.2019-0492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964136PMC
January 2020

Multi-institutional Development and External Validation of a Nomogram to Predict Recurrence After Curative Resection of Pancreatic Neuroendocrine Tumors.

Ann Surg 2019 Sep 24. Epub 2019 Sep 24.

Unit of General and Pancreatic Surgery, University and Hospital Trust of Verona, Italy.

Objective: To develop a nomogram estimating the probability of recurrence free at 5 years after resection for localized grade 1 (G1)/ grade 2 (G2) pancreatic neuroendocrine tumors (PanNETs).

Background: Among patients undergoing resection of PanNETs, approximately 17% experience recurrence. It is not established which patients are at risk, with no consensus on optimal follow-up.

Method: A multi-institutional database of patients with G1/G2 PanNETs treated at 2 institutions was used to develop a nomogram estimating the rate of freedom from recurrence at 5 years after curative resection. A second cohort of patients from 3 additional institutions was used to validate the nomogram. Prognostic factors were assessed by univariate analysis using Cox regression model. The nomogram was internally validated using bootstrap resampling method and on the external cohort. Performance was assessed by concordance index (c-index) and a calibration curve.

Results: The nomogram was constructed using a cohort of 632 patients. Overall, 68% of PanNETs were G1, the median follow-up was 51 months, and we observed 74 recurrences. Variables included in the nomogram were the number of positive nodes, tumor diameter, Ki-67, and vascular/perineural invasion. The model bias-corrected c-index from the internal validation was 0.85, which was higher than European Neuroendocrine Tumors Society/American Joint Committee on Cancer 8th staging scheme (c-index 0.76, P = <0.001). On the external cohort of 328 patients, the nomogram c-index was 0.84 (95% confidence interval 0.79-0.88).

Conclusion: Our externally validated nomogram predicts the probability of recurrence-free survival at 5 years after PanNETs curative resection, with improved accuracy over current staging systems. Estimating individual recurrence risk will guide the development of personalized surveillance programs after surgery.
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http://dx.doi.org/10.1097/SLA.0000000000003579DOI Listing
September 2019

Long-Term Oncologic Outcomes After Curative Resection of Familial Medullary Thyroid Carcinoma.

Ann Surg Oncol 2019 Dec 23;26(13):4423-4429. Epub 2019 Sep 23.

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

Introduction: Long-term outcomes after curative resection in patients with germline RET mutations and medullary thyroid cancer (MTC) are highly variable and mutation-specific oncologic outcomes are not well-described.

Methods: Sixty-six patients identified from 1986 to 2017 from a single-institution cancer database were assessed for recurrence and survival using Kaplan-Meier estimates, and correlated with clinicopathologic features using log-rank or Cox proportional hazards.

Results: Median follow-up was 9.3 years (range 0.3-31.5), median tumor diameter was 1.5 cm (range 0.1-7.5), and preoperative calcitonin was known in 41 patients [median 636 (range 0-9600)]. Overall survival (OS) of the cohort was 94% at 10 years, the cumulative incidence of locoregional recurrence was 38% at 10 years, and 19/24 (79%) patients underwent repeat neck operation. The cumulative incidence of distant recurrence was 27% at 10 years. Predictors of distant recurrence were tumor size, positive lymph nodes, and pre- and postoperative carcinoembryonic antigen, but not calcitonin. M918T mutation-bearing patients had 10-year distant recurrence-free survival of 0%, compared with 83% in all other patients (p < 0.001), and equivalent 10-year OS (100% vs. 92%; p = 0.49).

Conclusions: Structural and metastatic recurrence is common in patients with germline RET mutations, and MTC and can occur 20 years after initial treatment, however survival remains high. Management should focus on optimal surveillance strategies and long-term control of structural disease.
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http://dx.doi.org/10.1245/s10434-019-07869-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876629PMC
December 2019