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Volume 21 (2023): Issue 7 (Jul 2023)

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Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology

E. Gabriela Chiorean, Marco Del Chiaro, Margaret A. Tempero, Mokenge P. Malafa, Al B. Benson III, Dana B. Cardin, Jared A. Christensen, Vincent Chung, Brian Czito, Mary Dillhoff, Timothy R. Donahue, Efrat Dotan, Christos Fountzilas, Evan S. Glazer, Jeffrey Hardacre, William G. Hawkins, Kelsey Klute, Andrew H. Ko, John W. Kunstman, Noelle LoConte, Andrew M. Lowy, Ashiq Masood, Cassadie Moravek, Eric K. Nakakura, Amol K. Narang, Lorenzo Nardo, Jorge Obando, Patricio M. Polanco, Sushanth Reddy, Marsha Reyngold, Courtney Scaife, Jeanne Shen, Mark J. Truty, Charles Vollmer Jr, Robert A. Wolff, Brian M. Wolpin, Beth McCullough RN, Senem Lubin, and Susan D. Darlow

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

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Cardiovascular Implications of Vascular Endothelial Growth Factor Inhibition Among Adolescents/Young Adults in ECOG-ACRIN E2805

Wendy J. Bottinor, Yael Flamand, Naomi B. Haas, Anne M. ONeill, Robert S. DiPaola, Pearl Subramanian, David Cella, W. Gregory Hundley, Lynne I. Wagner, John M. Salsman, and Bonnie Ky

Background: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among adolescents and young adults (AYAs) diagnosed with cancer. The aim of this study was to assess the incidence and predictors of left ventricular systolic dysfunction (LVSD) and hypertension among AYAs receiving VEGF inhibition compared with non-AYAs. Methods: This retrospective analysis used data from the ASSURE trial ( identifier: NCT00326898), in which participants with nonmetastatic, high-risk, renal cell cancer were randomized to sunitinib, sorafenib, or placebo. The incidence of LVSD (left ventricular ejection fraction decrease >15%) and hypertension (blood pressure ≥140/90 mm Hg) were compared using nonparametric tests. Multivariable logistic regression examined the association between AYA status, LVSD, and hypertension while adjusting for clinical factors. Results: AYAs represented 7% (103/1,572) of the population. Over a study treatment period of 54 weeks, the incidence of LVSD was not significantly different among AYAs (3%; 95% CI, 0.6%–8.3%) versus non-AYAs (2%; 95% CI, 1.2%–2.7%). The incidence of hypertension was significantly lower among AYAs (18%; 95% CI, 7.5%–33.5%) compared with non-AYAs (46%; 95% CI, 41.9%–50.4%) in the placebo arm. In the sunitinib and sorafenib groups, the incidence of hypertension for AYAs compared with non-AYAs was 29% (95% CI, 15.1%–47.5%) versus 47% (95% CI, 42.3%–51.7%), and 54% (95% CI, 33.9%–72.5%) versus 63% (95% CI, 58.6%–67.7%), respectively. AYA status (odds ratio, 0.48; 95% CI, 0.31–0.75) and female sex (odds ratio, 0.74; 95% CI, 0.59–0.92) were each associated with a lower risk of hypertension. Conclusions: LVSD and hypertension were prevalent among AYAs. CVD among AYAs is only partially explained by cancer therapy. Understanding CVD risk among AYA cancer survivors is important for promoting cardiovascular health in this growing population.

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Constitutional MLH1 Methylation Is a Major Contributor to Mismatch Repair–Deficient, MLH1-Methylated Colorectal Cancer in Patients Aged 55 Years and Younger

Megan P. Hitchins, Estela Dámaso, Rocio Alvarez, Lisa Zhou, Yajing Hu, Marcio A. Diniz, Marta Pineda, Gabriel Capella, Rachel Pearlman, and Heather Hampel

Background: Most mismatch repair–deficient (MMRd) colorectal cancer (CRC) cases arise sporadically, associated with somatic MLH1 methylation, whereas approximately 20% have germline mismatch repair pathogenic variants causing Lynch syndrome (LS). Universal screening of incident CRC uses presence of MLH1 methylation in MMRd tumors to exclude sporadic cases from germline testing for LS. However, this overlooks rare cases with constitutional MLH1 methylation (epimutation), a poorly recognized mechanism for LS. We aimed to assess the frequency and age distribution of constitutional MLH1 methylation among incident CRC cases with MMRd, MLH1-methylated tumors. Methods: In retrospective population-based studies, we selected all CRC cases with MMRd, MLH1-methylated tumors, regardless of age, prior cancer, family history, or BRAF V600E status, from the Columbus-area HNPCC study (Columbus) and Ohio Colorectal Cancer Prevention Initiative (OCCPI) cohorts. Blood DNA was tested for constitutional MLH1 methylation by pyrosequencing and real-time methylation-specific PCR, then confirmed with bisulfite-sequencing. Results: Results were achieved for 95 of 98 Columbus cases and all 281 OCCPI cases. Constitutional MLH1 methylation was identified in 4 of 95 (4%) Columbus cases, ages 34, 38, 52, and 74 years, and 4 of 281 (1.4%) OCCPI cases, ages 20, 34, 50, and 55 years, with 3 showing low-level mosaic methylation. Mosaicism in blood and normal colon, plus tumor loss of heterozygosity of the unmethylated allele, demonstrated causality in 1 case with sample availability. Age stratification showed high rates of constitutional MLH1 methylation among younger patients. In the Columbus and OCCPI cohorts, respectively, these rates were 67% (2 of 3) and 25% (2 of 8) of patients aged <50 years but with half of the cases missed, and 75% (3 of 4) and 23.5% (4 of 17) of patients aged ≤55 years with most cases detected. Conclusions: Although rare overall, a significant proportion of younger patients with MLH1-methylated CRC had underlying constitutional MLH1 methylation. Routine testing for this high-risk mechanism is warranted in patients aged ≤55 years for a timely and accurate molecular diagnosis that will significantly alter their clinical management while minimizing additional testing.

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Determining PARP Inhibition as a Treatment Strategy in Melanoma Based on Homologous Recombination Deficiency–Related Loss of Heterozygosity

Alice Zhou, Omar Butt, Michael Ansstas, Elizabeth Mauer, Karam Khaddour, and George Ansstas

There is a lack of effective treatments for immunotherapy-refectory melanoma. Although PARP inhibitors (PARPi) are an effective treatment strategy in cancers with homologous recombination deficiency (HRD), determining HRD status is challenging in melanoma. Here, we chart the longitudinal relationship between PARPi response and HRD scores derived from genome-wide loss of heterozygosity (LOH) in 4 patients with metastatic melanoma. When next examining 933 melanoma cases, using an updated threshold, we observed HRD-related LOH (HRD-LOH) in nearly one-third of all cases compared with <10% using traditional gene panels. Taken together, HRD-LOH in refractory melanoma is both a common occurrence and a potential biomarker for response to PARPi.

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A Glimpse Into the Future

Margaret Tempero

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Highlights of the NCCN Oncology Research Program

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Impact of Asian Race on Prognosis in De Novo Metastatic Prostate Cancer

Xudong Ni, Michael Luu, Weiwei Ma, Tingwei Zhang, Yu Wei, Stephen J. Freedland, Dingwei Ye, Timothy J. Daskivich, and Yao Zhu

Background: Little is known about the impact of Asian race on the long-term survival outcomes of males with de novo metastatic prostate cancer (PCa). Understanding racial disparities in survival is critical for accurate prognostic risk stratification and for informing the design of multiregional clinical trials. Methods: This multiple-cohort study included individual patient-level data for males with de novo metastatic PCa from the following 3 cohorts: LATITUDE clinical trial data (n=1,199), the SEER program (n=15,476), and the National Cancer Database (NCDB; n=10,366). Primary outcomes were overall survival (OS) in LATITUDE and NCDB and OS and cancer-specific survival in SEER. Results: Across all 3 cohorts, Asian patients diagnosed with de novo metastatic PCa had better survival than white patients. In LATITUDE, median OS was significantly longer in Asian versus white patients in the androgen deprivation therapy (ADT) + abiraterone + prednisone group (not reached vs 43.8 months; hazard ratio [HR], 0.45; 95% CI, 0.28–0.73; P=.001) as well as in the ADT + placebo group (57.6 vs 32.7 months; HR, 0.51; 95% CI, 0.33–0.78; P=.002). In SEER, among all patients diagnosed with de novo metastatic PCa, median OS was significantly longer in Asian versus white males (49 vs 39 months; HR, 0.76; 95% CI, 0.68–0.84; P<.001). Among those who received chemotherapy, Asian patients again had longer OS (52 vs 42 months; HR, 0.71; 95% CI, 0.52–0.96; P=.025). Using data on cancer-specific survival in SEER resulted in similar conclusions. In NCDB, Asian patients also had longer OS than white patients in aggregate and in subgroups of males treated with ADT or chemotherapy (aggregate: 38 vs 26 months; HR, 0.72; 95% CI, 0.62–0.83; P<.001; ADT subgroup: 41 vs 26 months; HR, 0.71; 95% CI, 0.60–0.84; P<.001; chemotherapy subgroup: 34 vs 25 months; HR, 0.67; 95% CI, 0.57–0.78; P<.001). Conclusions: Asian males have better OS and cancer-specific survival than white males with metastatic PCa across different treatment regimens. This should be considered when assessing prognosis and in designing multinational clinical trials.

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NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023

Featured Updates to the NCCN Guidelines

Al B. Benson III, Michael I. D’Angelica, Thomas Abrams, Daniel E. Abbott, Aijaz Ahmed, Daniel A. Anaya, Robert Anders, Chandrakanth Are, Melinda Bachini, David Binder, Mitesh Borad, Christopher Bowlus, Daniel Brown, Adam Burgoyne, Jason Castellanos, Prabhleen Chahal, Jordan Cloyd, Anne M. Covey, Evan S. Glazer, William G. Hawkins, Renuka Iyer, Rojymon Jacob, Lawrence Jennings, R. Kate Kelley, Robin Kim, Matthew Levine, Manisha Palta, James O. Park, Steven Raman, Sanjay Reddy, Sean Ronnekleiv-Kelly, Vaibhav Sahai, Gagandeep Singh, Stacey Stein, Anita Turk, Jean-Nicolas Vauthey, Alan P. Venook, Adam Yopp, Nicole McMillian, Ryan Schonfeld, and Cindy Hochstetler

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.