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Ryan M. Kahn, Sushmita Gordhandas, Emeline Aviki, and Kara Long Roche

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Laura M. Spring, Yael Bar, and Steven J. Isakoff

The role of neoadjuvant therapy (NAT) for localized breast cancer has evolved tremendously over the past several years. Currently, NAT is the preferred option for high-risk early triple-negative (TN) and HER2-positive (HER2+) breast cancers and is indicated for some estrogen receptor–positive (ER+) breast cancers. In addition to traditional absolute indications for NAT, relative indications such as the assessment of outcomes at the time of surgery and guidance of treatment escalation and de-escalation have greatly evolved in recent years. Pathologic complete response (pCR) and the Residual Cancer Burden (RCB) index are highly prognostic for disease recurrence and survival, mainly in patients with TN or HER2+ disease. Furthermore, post-NAT escalation strategies have been shown to improve long-term outcomes of patients who do not achieve pCR. Additionally, by allowing the direct assessment of drug effect on the tumor, the neoadjuvant setting has become an attractive setting for the exploration of novel agents and the identification of predictive biomarkers. Neoadjuvant trial design has also evolved, using adaptive treatment approaches that enable treatment de-escalation or escalation based on response. However, despite multiple practice-changing neoadjuvant trials and the addition of various new agents to the neoadjuvant setting for early breast cancer, many key questions remain. For example, patient selection for neoadjuvant immunotherapy in TN breast cancer, de-escalation methods in HER2+ breast cancer, and the use of gene expression profiles to guide NAT recommendations in ER+ breast cancer. This article reviews the current approach for NAT in localized breast cancer as well as evolving NAT strategies, the key remaining challenges, and the ongoing work in the field.

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Abi Vijenthira, Lee Mozessohn, Chenthila Nagamuthu, Ning Liu, Danielle Blunt, Shabbir Alibhai, Anca Prica, and Matthew C. Cheung

Background: The objectives of this study were to determine whether frailty is associated with survival in a population-based sample of patients with diffuse large B-cell lymphoma (DLBCL) and to describe the healthcare utilization patterns of frail versus nonfrail patients during treatment. Methods: A retrospective cohort study was conducted using population-based data in Ontario, Canada. Patients aged ≥66 years diagnosed between 2006 and 2017 with DLBCL or transformed follicular lymphoma who received first-line curative-intent chemoimmunotherapy were included. Frailty was defined using a modified version of a generalizable frailty index developed for use with Ontario administrative data. Cox regression was performed to examine the association between frailty and 1-year mortality. Results: A total of 5,527 patients were included (median age, 75 years [interquartile range, 70–80 years]; 48% female), of whom 2,699 (49%) were classified as frail. Within 1 year of first-line treatment, 32% (n=868) of frail patients had died compared with 20% (n=553) of nonfrail patients (unadjusted hazard ratio, 1.8; 95% CI, 1.6–2.0; P<.0001). Frail patients had higher healthcare utilization during treatment, with most hospitalizations related to infection and/or lymphoma. In multivariable modeling controlling for age, inpatient diagnosis, number of chemoimmunotherapy cycles received, comorbidity burden, and healthcare utilization, frailty remained independently associated with 1-year mortality (adjusted hazard ratio, 1.5; 95% CI, 1.3–1.7; P<.0001). Conclusions: In a population-based sample of older adult patients with DLBCL receiving front-line curative-intent therapy, half were classified as frail, and their adjusted relative rate of death in the first year after starting treatment was 50% higher than that of nonfrail patients. Frailty seems to be associated with poor treatment tolerance and a higher likelihood of requiring acute hospital-based care.

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Margaret Tempero

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Yifan Wang, Adeline Cuggia, Yen-I Chen, Josée Parent, Agatha Stanek, Robert E. Denroche, Amy Zhang, Robert C. Grant, Céline Domecq, Bryn Golesworthy, Chaya Shwaartz, Ayelet Borgida, Spring Holter, Julie M. Wilson, George Chong, Grainne M. O’Kane, Jennifer J. Knox, Sandra E. Fischer, Steven Gallinger, Zu-Hua Gao, William D. Foulkes, Kevin A. Waschke, and George Zogopoulos

Background: Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at increased risk of developing PC. These high-risk individuals (HRIs) may benefit from PC surveillance. Methods: A PC surveillance program was developed to evaluate the detection of premalignant lesions and early-stage PCs using biannual imaging and to determine whether locally advanced or metastatic PCs develop despite biannual surveillance. From January 2013 to April 2020, asymptomatic HRIs were enrolled and followed with alternating MRI and endoscopic ultrasound every 6 months. Results: Of 75 HRIs, 43 (57.3%) had a germline mutation in a PC susceptibility gene and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 individuals (34.7%), but only 2 developed progressive lesions. One patient with Peutz-Jeghers syndrome (PJS) developed locally advanced PC arising from a BD-IPMN. Whole-genome sequencing of this patient’s PC and of a second patient with PJS-associated PC from the same kindred revealed biallelic inactivation of STK11 in a KRAS-independent manner. A review of 3,853 patients from 2 PC registries identified an additional patient with PJS-associated PC. All 3 patients with PJS developed advanced PC consistent with the malignant transformation of an underlying BD-IPMN in <6 months. The other surveillance patient with a progressive lesion had FPC and underwent resection of a mixed-type IPMN that harbored polyclonal KRAS mutations. Conclusions: PC surveillance identifies a high prevalence of BD-IPMNs in HRIs. Patients with PJS with BD-IPMNs may be at risk for accelerated malignant transformation.

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William G. Wierda, Jennifer Brown, Jeremy S. Abramson, Farrukh Awan, Syed F. Bilgrami, Greg Bociek, Danielle Brander, Asher A. Chanan-Khan, Steve E. Coutre, Randall S. Davis, Herbert Eradat, Christopher D. Fletcher, Sameh Gaballa, Armin Ghobadi, Muhammad Saad Hamid, Francisco Hernandez-Ilizaliturri, Brian Hill, Paul Kaesberg, Manali Kamdar, Lawrence D. Kaplan, Nadia Khan, Thomas J. Kipps, Shuo Ma, Anthony Mato, Claudio Mosse, Stephen Schuster, Tanya Siddiqi, Deborah M. Stephens, Chaitra Ujjani, Nina Wagner-Johnston, Jennifer A. Woyach, J. Christine Ye, Mary A. Dwyer, and Hema Sundar

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

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Yan Hiu Athena Lee, Jiandong Zhou, Jeremy Man Ho Hui, Xuejin Liu, Teddy Tai Loy Lee, Kyle Hui, Jeffrey Shi Kai Chan, Abraham Ka Chung Wai, Wing Tak Wong, Tong Liu, Kenrick Ng, Sharen Lee, Edward Christopher Dee, Qingpeng Zhang, and Gary Tse

Background: The aim of this study was to compare the risks of new-onset prostate cancer between metformin and sulfonylurea users with type 2 diabetes mellitus (T2DM). Methods: This population-based retrospective cohort study included male patients with T2DM presenting to public hospitals/clinics in Hong Kong between January 1, 2000, and December 31, 2009. We only included patients prescribed either, but not both, metformin or sulfonylurea. All patients were followed up until December 31, 2019. The primary outcome was new-onset prostate cancer and the secondary outcome was all-cause mortality. One-to-one propensity score matching was performed between metformin and sulfonylurea users based on demographics, comorbidities, antidiabetic and cardiovascular medications, fasting blood glucose level, and hemoglobin A1c level. Subgroup analyses based on age and use of androgen deprivation therapy were performed. Results: The final study cohort consisted of 25,695 metformin users (mean [SD] age, 65.2 [11.8] years) and 25,695 matched sulfonylurea users (mean [SD] age, 65.3 [11.8] years) with a median follow-up duration of 119.6 months (interquartile range, 91.7–139.6 months) after 1:1 propensity score matching of 66,411 patients. Metformin users had lower risks of new-onset prostate cancer (hazard ratio, 0.80; 95% CI, 0.69–0.93; P=.0031) and all-cause mortality (hazard ratio, 0.89; 95% CI, 0.86–0.92; P<.0001) than sulfonylurea users. Metformin use was more protective against prostate cancer but less protective against all-cause mortality in patients aged <65 years (P for trend <.0001 for both) compared with patients aged ≥65 years. Metformin users had lower risk of all-cause mortality than sulfonylurea users, regardless of the use of androgen deprivation therapy (P for trend <.0001) among patients who developed prostate cancer. Conclusions: Metformin use was associated with significantly lower risks of new-onset prostate cancer and all-cause mortality than sulfonylurea use in male patients with T2DM.