Racial Differences in 21-Gene Recurrence Scores Among Patients With Hormone Receptor–Positive, Node-Negative Breast Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-17 Andreana N. Holowatyj; Michele L. Cote; Julie J. Ruterbusch; Kristina Ghanem; Ann G. Schwartz; Fawn D. Vigneau; David H. Gorski; Kristen S. Purrington
Purpose The 21-gene recurrence score (RS) breast cancer assay is clinically used to quantify risk of 10-year distant recurrence by category (low, < 18; intermediate, 18 to 30; high, ≥ 31) for treatment management among women diagnosed with hormone receptor–positive, human epidermal growth factor receptor 2–negative, lymph node–negative breast cancer. Although non-Hispanic black (NHB) women have worse prognosis compared with non-Hispanic white (NHW) women, the equivalency of 21-gene RS across racial groups remains unknown. Patients and Methods Using the Metropolitan Detroit Cancer Surveillance System, we identified women who were diagnosed with hormone receptor–positive, human epidermal growth factor receptor 2–negative, lymph node–negative invasive breast cancer between 2010 and 2014. Multinomial logistic regression was used to quantify racial differences in 21-gene RS category. Results We identified 2,216 women (1,824 NHW and 392 NHB) with invasive breast cancer who met clinical guidelines for and underwent 21-gene RS testing. The mean RS was significantly higher in NHBs compared with NHWs (19.3 v 17.0, respectively; P = .0003), where NHBs were more likely to present with high-risk tumors compared with NHWs (14.8% v 8.3%, respectively; P = .0004). These differences were limited to patients younger than 65 years at diagnosis, among whom NHBs had significantly higher RS compared with NHWs (20 to 49 years: 23.6 v 17.3, respectively; P < .001 and 50 to 64 years: 19.6 v 17.4, respectively; P = .023). NHBs remained more likely to have high-risk tumors compared with NHWs after adjusting for age, clinical stage, tumor grade, and histology (odds ratio [OR], 1.75; 95% CI, 1.18 to 2.59). Conclusion NHBs who met clinical criteria for 21-gene RS testing had tumors with higher estimated risks of distant recurrence compared with NHWs. Further study is needed to elucidate whether differences in recurrence are observed for these women, which would have clinical implications for 21-gene RS calibration and treatment recommendations in NHB patients.
Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-17 F. Stephen Hodi; Marcus Ballinger; Benjamin Lyons; Jean-Charles Soria; Mizuki Nishino; Josep Tabernero; Thomas Powles; David Smith; Axel Hoos; Chris McKenna; Ulrich Beyer; Ina Rhee; Gregg Fine; Nathan Winslow; Daniel S. Chen; Jedd D. Wolchok
Purpose Treating solid tumors with cancer immunotherapy (CIT) can result in unconventional responses and overall survival (OS) benefits that are not adequately captured by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. We describe immune-modified RECIST (imRECIST) criteria, designed to better capture CIT responses. Patients and Methods Atezolizumab data from clinical trials in non–small-cell lung cancer, metastatic urothelial carcinoma, renal cell carcinoma, and melanoma were evaluated. Modifications to imRECIST versus RECIST v1.1 included allowance for best overall response after progressive disease (PD) and changes in PD definitions per new lesions (NLs) and nontarget lesions. imRECIST progression-free survival (PFS) did not count initial PD as an event if the subsequent scan showed disease control. OS was evaluated using conditional landmarks in patients whose PFS differed by imRECIST versus RECIST v1.1. Results The best overall response was 1% to 2% greater, the disease control rate was 8% to 13% greater, and the median PFS was 0.5 to 1.5 months longer per imRECIST versus RECIST v1.1. Extension of imRECIST PFS versus RECIST v1.1 PFS was associated with longer or similar OS. Patterns of progression analysis revealed that patients who developed NLs without target lesion (TL) progression had a similar or shorter OS compared with patients with RECIST v1.1 TL progression. Patients infrequently experienced a spike pattern (TLs increase, then decrease) but had longer OS than patients without TL reversion. Conclusion Evaluation of PFS and patterns of response and progression revealed that allowance for TL reversion from PD per imRECIST may better identify patients with OS benefit. Progression defined by the isolated appearance of NLs, however, is not associated with longer OS. These results may inform additional modifications to radiographic criteria (including imRECIST) to better reflect efficacy with CIT agents.
Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-17 David S. Siegel; Meletios A. Dimopoulos; Heinz Ludwig; Thierry Facon; Hartmut Goldschmidt; Andrzej Jakubowiak; Jesus San-Miguel; Mihaela Obreja; Julie Blaedel; A. Keith Stewart
Purpose In the ASPIRE study of carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide plus dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma, progression-free survival was significantly improved in the carfilzomib group (hazard ratio, 0.69; two-sided P < .001). This prespecified analysis reports final overall survival (OS) data and updated safety results. Patients and Methods Adults with relapsed multiple myeloma (one to three prior lines of therapy) were eligible and randomly assigned at a one-to-one ratio to receive KRd or Rd in 28-day cycles until withdrawal of consent, disease progression, or occurrence of unacceptable toxicity. After 18 cycles, all patients received Rd only. Progression-free survival was the primary end point; OS was a key secondary end point. OS was compared between treatment arms using a stratified log-rank test. Results Median OS was 48.3 months (95% CI, 42.4 to 52.8 months) for KRd versus 40.4 months (95% CI, 33.6 to 44.4 months) for Rd (hazard ratio, 0.79; 95% CI, 0.67 to 0.95; one-sided P = .0045). In patients receiving one prior line of therapy, median OS was 11.4 months longer for KRd versus Rd; it was 6.5 months longer for KRd versus Rd among patients receiving ≥ two prior lines of therapy. Rates of treatment discontinuation because of adverse events (AEs) were 19.9% (KRd) and 21.5% (Rd). Grade ≥ 3 AE rates were 87.0% (KRd) and 83.3% (Rd). Selected grade ≥ 3 AEs of interest (grouped terms; KRd v Rd) included acute renal failure (3.8% v 3.3%), cardiac failure (4.3% v 2.1%), ischemic heart disease (3.8% v 2.3%), hypertension (6.4% v 2.3%), hematopoietic thrombocytopenia (20.2% v 14.9%), and peripheral neuropathy (2.8% v 3.1%). Conclusion KRd demonstrated a statistically significant and clinically meaningful reduction in the risk of death versus Rd, improving survival by 7.9 months. The KRd efficacy advantage is most pronounced at first relapse.
Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-17 Kenneth Anderson; Nofisat Ismaila; Patrick J. Flynn; Susan Halabi; Sundar Jagannath; Mohammed S. Ogaily; Jim Omel; Noopur Raje; G. David Roodman; Gary C. Yee; Robert A. Kyle
Purpose To update guideline recommendations on the role of bone-modifying agents in multiple myeloma. Methods An update panel conducted a targeted systematic literature review by searching PubMed and the Cochrane Library for randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies. Results Thirty-five relevant studies were identified, and updated evidence supports the current recommendations. Recommendations For patients with active symptomatic multiple myeloma that requires systemic therapy with or without evidence of lytic destruction of bone or compression fracture of the spine from osteopenia on plain radiograph(s) or other imaging studies, intravenous administration of pamidronate 90 mg over at least 2 hours or zoledronic acid 4 mg over at least 15 minutes every 3 to 4 weeks is recommended. Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative. Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting. The update panel recommends that clinicians consider reducing the initial pamidronate dose in patients with preexisting renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The update panel suggests that bone-modifying treatment continue for up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. Continuous use is at the discretion of the treating physician and the risk of ongoing skeletal morbidity. Retreatment should be initiated at the time of disease relapse. The update panel discusses measures regarding osteonecrosis of the jaw. Additional information is available at www.asco.org/hematologic-malignancies-guidelines and www.asco.org/guidelineswiki.
Front-Line Treatment Options for Chronic-Phase Chronic Myeloid Leukemia J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Neil P. Shah
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 40-year-old woman with a past medical history of hypertension and occasional premature ventricular contractions was found on routine blood work in June 2011 to have mild thrombocytosis, with a platelet count of 405,000. In November 2011, repeat analysis revealed a platelet count of 433,000, and by February 2012 her platelet count was 509,000. She had no evidence of leukocytosis or anemia and no symptoms of early satiety, night sweats, pruritus, or erythromelalgia. She was referred to a hematologist for evaluation of persistent isolated thrombocytosis in March 2012. Her spleen was not palpable, and a quantitative polymerase chain reaction (PCR) test for JAK2/V617F was negative. A bone marrow biopsy and aspiration revealed a mildly hypercellular marrow (70% to 80% cellularity), with an elevated myeloid:erythroid ratio of 5:1, increased megakaryocytes including micromegakaryocytes in the absence of increased blasts. Cytogenetic analysis revealed the presence of the Philadelphia chromosome translocation in 17 out of 20 metaphases. The remaining three metaphases were normal karyotype. Quantitative PCR for BCR-ABL1 yielded a value of 29.6% on the International Scale.
Impact of Prognostic Discussions on the Patient-Physician Relationship: Prospective Cohort Study J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Joshua J. Fenton; Paul R. Duberstein; Richard L. Kravitz; Guibo Xing; Daniel J. Tancredi; Kevin Fiscella; Supriya Mohile; Ronald M. Epstein
Purpose Some research has suggested that discussion of prognosis can disrupt the patient-physician relationship. This study assessed whether physician discussion of prognosis is associated with detrimental changes in measures of the strength of the patient-physician relationship. Methods This was a longitudinal cohort study of 265 adult patients with advanced cancer who visited 38 oncologists within community- and hospital-based cancer clinics in Western New York and Northern California. Prognostic discussion was assessed by coding transcribed audio-recorded visits using the Prognostic and Treatment Choices (PTCC) scale and by patient survey at 3 months after the clinic visit. Changes in the strength of the patient-physician relationship were computed as differences in patient responses to The Human Connection and the Perceived Efficacy in Patient-Physician Interactions scales from baseline to 2 to 7 days and 3 months after the clinic visit. Results Prognostic discussion was not associated with a temporal decline in either measure. Indeed, a one-unit increase in PTCC during the audio-recorded visit was associated with improvement in The Human Connection scale at 2 to 7 days after the visit (parameter estimate, 0.10; 95% CI, −0.02 to 0.23) and 3 months after the visit (parameter estimate, 0.18; 95% CI, 0.02 to 0.35) relative to baseline. Standardized effect sizes (SES) associated with an increase of two standard deviations in the PTCC at each time point were consistent with small beneficial effects (SES, 0.14 [95% CI, −0.02 to 0.29] at 2 to 7 days; SES, 0.24 [95% CI, 0.02 to 0.45] at 3 months), and lower bounds of CIs indicated that substantial detrimental effects of prognostic discussion were unlikely. Conclusion Prognostic discussion is not intrinsically harmful to the patient-physician relationship and may even strengthen the therapeutic alliance between patients and oncologists.
Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Jorge E. Cortes; Carlo Gambacorti-Passerini; Michael W. Deininger; Michael J. Mauro; Charles Chuah; Dong-Wook Kim; Irina Dyagil; Nataliia Glushko; Dragana Milojkovic; Philipp le Coutre; Valentin Garcia-Gutierrez; Laurence Reilly; Allison Jeynes-Ellis; Eric Leip; Nathalie Bardy-Bouxin; Andreas Hochhaus; Tim H. Brümmendorf
Purpose Bosutinib is a potent dual SRC/ABL kinase inhibitor approved for adults with Philadelphia chromosome–positive chronic myeloid leukemia (CML) resistant and /or intolerant to prior therapy. We assessed the efficacy and safety of bosutinib versus imatinib for first-line treatment of chronic-phase CML. Methods In this ongoing, multinational, phase III study, 536 patients with newly diagnosed chronic-phase CML were randomly assigned 1:1 to receive 400 mg of bosutinib once daily (n = 268) or imatinib (n = 268). Per protocol, efficacy was assessed in patients who were Philadelphia chromosome–positive with typical (e13a2/e14a2) transcripts (bosutinib, n = 246; imatinib, n = 241). Patients with Philadelphia chromosome–negative–/BCR-ABL1–positive status and those with unknown Philadelphia chromosome status and/or atypical BCR-ABL1 transcript type were excluded from this population. Results The major molecular response (MMR) rate at 12 months (primary end point) was significantly higher with bosutinib versus imatinib (47.2% v 36.9%, respectively; P = .02), as was complete cytogenetic response (CCyR) rate by 12 months (77.2% v 66.4%, respectively; P = .0075). Cumulative incidence was favorable with bosutinib (MMR: hazard ratio, 1.34; P = .0173; CCyR: hazard ratio, 1.38; P < .001), with earlier response times. Four patients (1.6%) receiving bosutinib and six patients (2.5%) receiving imatinib experienced disease progression to accelerated/blast phase. Among treated patients, 22.0% of patients receiving bosutinib and 26.8% of patients receiving imatinib discontinued treatment, most commonly for drug-related toxicity (12.7% and 8.7%, respectively). Grade ≥ 3 diarrhea (7.8% v 0.8%) and increased ALT (19.0% v 1.5%) and AST (9.7% v 1.9%) levels were more common with bosutinib. Cardiac and vascular toxicities were uncommon. Conclusion Patients who received bosutinib had significantly higher rates of MMR and CCyR and achieved responses faster than those who received imatinib. Consistent with the known safety profile, GI events and transaminase elevations were more common with bosutinib. Results indicate bosutinib may be an effective first-line treatment for chronic-phase CML.
Population-Based Study to Determine the Health System Costs of Using the 21-Gene Assay J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Nicole Mittmann; Craig C. Earle; Stephanie Y. Cheng; Jim A. Julian; Farah Rahman; Soo Jin Seung; Mark N. Levine
Purpose The 21-gene assay Oncotype Dx (Genomic Health, Redwood City, CA) test is used to aid the decision about chemotherapy in patients with hormone receptor–positive breast cancer who received endocrine therapy. Economic studies to support test adoption used decision-analytic models with assumptions and data derived from disparate sources. The objective was to evaluate whether the 21-gene assay test resulted in an overall cost expense or saving to the health system. Patients and Methods One thousand participants enrolled in a field evaluation study, were linked to population-level health system administrative databases, and were observed for 20 months. The cost for the cohort, which included the cost of the test, subsequent treatments received, and health care encounters, was determined. The cost in the absence of the test was compared with the pretest recommendation about chemotherapy from the field study for a base case and under scenarios that reflected different adjuvant chemotherapy use. Overall health system costs and incremental costs were calculated. Results The 21-gene assay resulted in a net decrease in chemotherapy use of 23%. For the base case incremental analysis, the actual overall health system cost of this cohort, including the cost of 21-gene assay, was $29.2 million compared with $26.2 million in the absence of the test—an increase of $3.1 million. For three of the four scenario analyses, the actual overall cost to the health system exceeded the estimated cost in the absence of the test. Results showed that, when at least half of the population received adjuvant chemotherapy, the cost increased to $30.2 million. Conclusion The use of real-world administrative data showed that, despite lower rates of chemotherapy use, the 21-gene assay test results in an overall incremental cost to the health care system in the short-term under most assumptions.
Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000) J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Martin Schrappe; Kirsten Bleckmann; Martin Zimmermann; Andrea Biondi; Anja Möricke; Franco Locatelli; Gunnar Cario; Carmelo Rizzari; Andishe Attarbaschi; Maria Grazia Valsecchi; Claus R. Bartram; Elena Barisone; Felix Niggli; Charlotte Niemeyer; Anna Maria Testi; Georg Mann; Ottavio Ziino; Beat Schäfer; Renate Panzer-Grümayer; Rita Beier; Rosanna Parasole; Gudrun Göhring; Wolf-Dieter Ludwig; Fiorina Casale; Paul-Gerhardt Schlegel; Giuseppe Basso; Valentino Conter
Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% (P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% (P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% (P = .06). Patients with ETV6-RUNX1–positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively (P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.
Outcome and Prognostic Factors in Stage III Favorable-Histology Wilms Tumor: A Report From the Children’s Oncology Group Study AREN0532 J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Conrad V. Fernandez; Elizabeth A. Mullen; Yueh-Yun Chi; Peter F. Ehrlich; Elizabeth J. Perlman; John A. Kalapurakal; Geetika Khanna; Arnold C. Paulino; Thomas E. Hamilton; Kenneth W. Gow; Zelig Tochner; Fredric A. Hoffer; Janice S. Withycombe; Robert C. Shamberger; Yeonil Kim; James I. Geller; James R. Anderson; Paul E. Grundy; Jeffrey S. Dome
Background The National Wilms Tumor Study (NWTS) approach to treating stage III favorable-histology Wilms tumor (FHWT) is Regimen DD4A (vincristine, dactinomycin, and doxorubicin) and radiation therapy. Further risk stratification is required to improve outcomes and reduce late effects. We evaluated clinical and biologic variables for patients with stage III FHWT without combined loss of heterozygosity (LOH) at chromosomes 1p and 16q treated in the Children’s Oncology Group protocol AREN0532. Methods From October 2006 to August 2013, 588 prospectively treated, centrally reviewed patients with stage III FHWT were treated with Regimen DD4A and radiation therapy. Tumor LOH at 1p and 16q was determined by microsatellite analysis. Ineligible patients (n = 5) and those with combined LOH 1p/16q (n = 40) were excluded. Results A total of 535 patients with stage III disease were studied. Median follow-up was 5.2 years (range, 0.2 to 9.5). Four-year event-free survival (EFS) and overall survival estimates were 88% (95% CI, 85% to 91%) and 97% (95% CI, 95% to 99%), respectively. A total of 58 of 66 relapses occurred in the first 2 years, predominantly pulmonary (n = 36). Eighteen patients died, 14 secondary to disease. A better EFS was associated with negative lymph node status (P < .01) and absence of LOH 1p or 16q (P < .01), but not with gross residual disease or peritoneal implants. In contrast, the 4-year EFS was only 74% in patients with combined positive lymph node status and LOH 1p or 16q. A total of 123 patients (23%) had delayed nephrectomy. Submitted delayed nephrectomy histology showed anaplasia (n = 8; excluded from survival analysis); low risk/completely necrotic (n = 7; zero relapses), intermediate risk (n = 63; six relapses), and high-risk/blastemal type (n=7; five relapses). Conclusion Most patients with stage III FHWT had good EFS/overall survival with DD4A and radiation therapy. Combined lymph node and LOH status was highly predictive of EFS and should be considered as a potential prognostic marker for future trials.
Effect of Prophylactic Human Papillomavirus (HPV) Vaccination on Oral HPV Infections Among Young Adults in the United States J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Anil K. Chaturvedi; Barry I. Graubard; Tatevik Broutian; Robert K.L. Pickard; Zhen-Yue Tong; Weihong Xiao; Lisa Kahle; Maura L. Gillison
Purpose The incidence of human papilloma virus (HPV)–positive oropharyngeal cancers has risen rapidly in recent decades among men in the United States. We investigated the US population–level effect of prophylactic HPV vaccination on the burden of oral HPV infection, the principal cause of HPV-positive oropharyngeal cancers. Methods We conducted a cross-sectional study of men and women 18 to 33 years of age (N = 2,627) within the National Health and Nutrition Examination Survey 2011 to 2014, a representative sample of the US population. Oral HPV infection with vaccine types 16, 18, 6, or 11 was compared by HPV vaccination status, as measured by self-reported receipt of at least one dose of the HPV vaccine. Analyses accounted for the complex sampling design and were adjusted for age, sex, and race. Statistical significance was assessed using a quasi-score test. Results Between 2011 and 2014, 18.3% of the US population 18 to 33 years of age reported receipt of at least one dose of the HPV vaccine before the age of 26 years (29.2% in women and 6.9% in men; P < .001). The prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated individuals (0.11% v 1.61%; Padj = .008), corresponding to an estimated 88.2% (95% CI, 5.7% to 98.5%) reduction in prevalence after model adjustment for age, sex, and race. Notably, the prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated men (0.0% v 2.13%; Padj = .007). Accounting for vaccine uptake, the population-level effect of HPV vaccination on the burden of oral HPV16/18/6/11 infections was 17.0% overall, 25.0% in women, and 6.9% in men. Conclusion HPV vaccination was associated with reduction in vaccine-type oral HPV prevalence among young US adults. However, because of low vaccine uptake, the population-level effect was modest overall and particularly low in men.
Effect of Neoadjuvant Chemoradiotherapy on Health-Related Quality of Life in Esophageal or Junctional Cancer: Results From the Randomized CROSS Trial J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Bo Jan Noordman; Mathilde G.E. Verdam; Sjoerd M. Lagarde; Maarten C.C.M. Hulshof; Pieter van Hagen; Mark I. van Berge Henegouwen; Bas P.L. Wijnhoven; Hanneke W.M. van Laarhoven; Grard A.P. Nieuwenhuijzen; Geke A.P. Hospers; Johannes J. Bonenkamp; Miguel A. Cuesta; Reinoud J.B. Blaisse; Olivier R. Busch; Fiebo J.W. ten Kate; Geert-Jan M. Creemers; Cornelis J.A. Punt; John Th.M. Plukker; Henk M.W. Verheul; Ernst J. Spillenaar Bilgen; Herman van Dekken; Maurice J.C. van der Sangen; Tom Rozema; Katharina Biermann; Jannet C. Beukema; Anna H.M. Piet; Caroline M. van Rij; Janny G. Reinders; Hugo W. Tilanus; Ewout W. Steyerberg; Ate van der Gaast; Mirjam A.G. Sprangers; J. Jan B. van Lanschot
Purpose To compare pre-agreed health-related quality of life (HRQOL) domains in patients with esophageal or junctional cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery or surgery alone. Secondary aims were to examine the effect of nCRT on HRQOL before surgery and the effect of surgery on HRQOL. Patients and Methods Patients were randomly assigned to nCRT (carboplatin plus paclitaxel with concurrent 41.4-Gy radiotherapy) followed by surgery or surgery alone. HRQOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and –Oesophageal Cancer Module (QLQ-OES24) questionnaires pretreatment and at 3, 6, 9, and 12 months postoperatively. The nCRT group also received preoperative questionnaires. Physical functioning (PF; QLQ-C30) and eating problems (EA; QLQ-OES24) were chosen as predefined primary end points. Predefined secondary end points were global QOL (GQOL; QLQ-C30), fatigue (FA; QLQ-C30), and emotional problems (EM; QLQ-OES24). Results A total of 363 patients were analyzed. No statistically significant differences in postoperative HRQOL were found between treatment groups. In the nCRT group, PF, EA, GQOL, FA, and EM scores deteriorated 1 week after nCRT (Cohen’s d: −0.93, P < .001; 0.47, P < .001; −0.84, P < .001; 1.45, P < .001; and 0.32, P = .001, respectively). In both treatment groups, all end points declined 3 months postoperatively compared with baseline (Cohen’s d: −1.00, 0.33, −0.47, −0.34, and 0.33, respectively; all P < .001), followed by a continuous gradual improvement. EA, GQOL, and EM were restored to baseline levels during follow-up, whereas PF and FA remained impaired 1 year postoperatively (Cohen’s d: 0.52 and −0.53, respectively; both P < .001). Conclusion Although HRQOL declined during nCRT, no effect of nCRT was apparent on postoperative HRQOL compared with surgery alone. In addition to the improvement in survival, these findings support the view that nCRT according to the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study–regimen can be regarded as a standard of care.
Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Milind Javle; Maeve Lowery; Rachna T. Shroff; Karl Heinz Weiss; Christoph Springfeld; Mitesh J. Borad; Ramesh K. Ramanathan; Lipika Goyal; Saeed Sadeghi; Teresa Macarulla; Anthony El-Khoueiry; Robin Kate Kelley; Ivan Borbath; Su Pin Choo; Do-Youn Oh; Philip A. Philip; Li-Tzong Chen; Thanyanan Reungwetwattana; Eric Van Cutsem; Kun-Huei Yeh; Kristen Ciombor; Richard S. Finn; Anuradha Patel; Suman Sen; Dale Porter; Randi Isaacs; Andrew X. Zhu; Ghassan K. Abou-Alfa; Tanios Bekaii-Saab
Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 (FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study (ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.
Platelet Transfusion for Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20 Charles A. Schiffer; Kari Bohlke; Meghan Delaney; Heather Hume; Anthony J. Magdalinski; Jeffrey J. McCullough; James L. Omel; John M. Rainey; Paolo Rebulla; Scott D. Rowley; Michael B. Troner; Kenneth C. Anderson
Purpose To provide evidence-based guidance on the use of platelet transfusion in people with cancer. This guideline updates and replaces the previous ASCO platelet transfusion guideline published initially in 2001. Methods ASCO convened an Expert Panel and conducted a systematic review of the medical literature published from September 1, 2014, through October 26, 2016. This review builds on two 2015 systematic reviews that were conducted by the AABB and the International Collaboration for Transfusion Medicine Guidelines. For clinical questions that were not addressed by the AABB and the International Collaboration for Transfusion Medicine Guidelines (the use of leukoreduction and platelet transfusion in solid tumors or chronic, stable severe thrombocytopenia) or that were addressed partially (invasive procedures), the ASCO search extended back to January 2000. Results The updated ASCO review included 24 more recent publications: three clinical practice guidelines, eight systematic reviews, and 13 observational studies. Recommendations The most substantial change to a previous recommendation involved platelet transfusion in the setting of hematopoietic stem-cell transplantation. Based on data from randomized controlled trials, adult patients who undergo autologous stem-cell transplantation at experienced centers may receive a platelet transfusion at the first sign of bleeding, rather than prophylactically. Prophylactic platelet transfusion at defined platelet count thresholds is still recommended for pediatric patients undergoing autologous stem-cell transplantation and for adult and pediatric patients undergoing allogeneic stem-cell transplantation. Other recommendations address platelet transfusion in patients with hematologic malignancies or solid tumors or in those who undergo invasive procedures. Guidance is also provided regarding the production of platelet products, prevention of Rh alloimmunization, and management of refractoriness to platelet transfusion (www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki).
Errata J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20
The August 10, 2017, article by Smith et al entitled “Participant-Reported Symptoms and Their Effect on Long-Term Adherence in the International Breast Cancer Intervention Study I (IBIS I)” (J Clin Oncol 35:2666-2673, 2017) was published with an error of omission.
Errata J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-20
The October 20, 2017, article by Hanna et al entitled “Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update” (J Clin Oncol 35:3484-3515, 2017) was published with an error.
Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma in Nonsurgically Managed Patients: Analysis of the National Cancer Database J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-12 Devalkumar J. Rajyaguru; Andrew J. Borgert; Angela L. Smith; Reggie M. Thomes; Patrick D. Conway; Thorvardur R. Halfdanarson; Mark J. Truty; A. Nicholas Kurup; Ronald S. Go
Purpose Data that guide selection of optimal local ablative therapy for the management localized hepatocellular carcinoma (HCC) are lacking. Because there are limited prospective comparative data for these treatment modalities, we aimed to compare the effectiveness of radiofrequency ablation (RFA) versus stereotactic body radiotherapy (SBRT) by using the National Cancer Database. Methods We conducted an observational study to compare the effectiveness of RFA versus SBRT in nonsurgically managed patients with stage I or II HCC. Overall survival was compared by using propensity score–weighted and propensity score–matched analyses based on patient-, facility-, and tumor-level characteristics. A sensitivity analysis was performed to evaluate the effect of severe fibrosis/cirrhosis. In addition, we performed exploratory analyses to determine the effectiveness of RFA and SBRT in clinically relevant patient subsets. Results Overall, 3,684 (92.6%) and 296 (7.4%) nonsurgically managed patients with stage I or II HCC received RFA or SBRT, respectively. After propensity matching, 5-year overall survival was 29.8% (95% CI, 24.5% to 35.3%) in the RFA group versus 19.3% (95% CI, 13.5% to 25.9%) in the SBRT group (P < .001). Inverse probability–weighted analysis yielded similar results. The benefit of RFA was consistent across all subgroups examined and was robust to the effects of severe fibrosis/cirrhosis. Conclusion Our study suggests that treatment with RFA yields superior survival compared with SBRT for nonsurgically managed patients with stage I or II HCC. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending local ablative therapy for localized unresectable HCC.
Quality of Life From Canadian Cancer Trials Group MA.17R: A Randomized Trial of Extending Adjuvant Letrozole to 10 Years J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-12 Julie Lemieux; Michael D. Brundage; Wendy R. Parulekar; Paul E. Goss; James N. Ingle; Kathleen I. Pritchard; Paul Celano; Hyman Muss; Julie Gralow; Kathrin Strasser-Weippl; Kate Whelan; Dongsheng Tu; Timothy J. Whelan
Purpose MA.17R was a Canadian Cancer Trials Group–led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor as adjuvant therapy for hormone receptor–positive breast cancer. Quality of life (QOL) was a secondary outcome measure of the study, and here, we report the results of these analyses. Methods QOL was measured using the Short Form-36 (SF-36; two summary scores and eight domains) and menopause-specific QOL (MENQOL; four symptom domains) at baseline and every 12 months up to 60 months. QOL assessment was mandatory for Canadian Cancer Trials Group centers but optional for centers in other groups. Mean change scores from baseline were calculated. Results One thousand nine hundred eighteen women were randomly assigned, and 1,428 women completed the baseline QOL assessment. Compliance with QOL measures was > 85%. Baseline summary scores for the SF-36 physical component summary (47.5 for letrozole and 47.9 for placebo) and mental component summary (55.5 for letrozole and 54.8 for placebo) were close to the population norms of 50. No differences were seen between groups in mean change scores for the SF-36 physical and mental component summaries and the other eight QOL domains except for the role-physical subscale. No difference was found in any of the four domains of the MENQOL Conclusion No clinically significant differences were seen in overall QOL measured by the SF-36 summary measures and MENQOL between the letrozole and placebo groups. The data indicate that continuation of aromatase inhibitor therapy after 5 years of prior treatment in the trial population was not associated with a deterioration of overall QOL.
What Happens When Proton Meets Randomization: Is There a Future for Proton Therapy? J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-12 Feng-Ming (Spring) Kong
The use of proton therapy has been a topic of debate for years. In the article that accompanies this editorial, Liao and colleagues1 report the first randomized study to assess the value of proton therapy compared with photon intensity-modulated radiotherapy (IMRT) in non–small-cell lung cancer (NSCLC). Completion of this study is not trivial because the evaluation of the benefit of a new technology rarely has been done during the century-long history of radiation oncology practice. A trial on the effectiveness of proton technology is particularly timely with the growing number of proton facilities in the United States and worldwide and its implication for value-based medicine.
Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 John D. Hainsworth; Funda Meric-Bernstam; Charles Swanton; Herbert Hurwitz; David R. Spigel; Christopher Sweeney; Howard Burris; Ron Bose; Bongin Yoo; Alisha Stein; Mary Beattie; Razelle Kurzrock
PurposeDetection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments.MethodsMyPathway (ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort.ResultsBetween April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2–amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non–small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%).ConclusionThe four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.
Development and Validation of a Risk Prediction Model for Acute Kidney Injury After the First Course of Cisplatin J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Shveta S. Motwani; Gearoid M. McMahon; Benjamin D. Humphreys; Ann H. Partridge; Sushrut S. Waikar; Gary C. Curhan
PurposeCisplatin-associated acute kidney injury (C-AKI) is common. We sought to develop and validate a predictive model for C-AKI after the first course of cisplatin.MethodsClinical and demographic data were collected on patients who received cisplatin between 2000 and 2016 at two cancer centers. C-AKI was defined as a 0.3 mg/dL rise in serum creatinine within 14 days of receiving cisplatin. Using multivariable logistic regression models with C-AKI as the primary outcome, we created a scoring model from the development cohort (DC) and tested it in the validation cohort (VC).ResultsC-AKI occurred in 13.6% of 2,118 patients in the DC and in 11.6% of 2,363 patients in the VC. Factors significantly associated with C-AKI included age 61 to 70 years (odds ratio [OR], 1.64 [95% CI, 1.21 to 2.23]; P = .001) and 71 to 90 years (OR, 2.97 [95% CI, 2.06 to 4.28]; P < .001) compared with ≤ 60 years; cisplatin dose 101 to 150 mg (OR, 1.58 [95% CI, 1.14 to 2.19]; P = .007) and > 150 mg (OR, 3.73 [95% CI, 2.68 to 5.20]; P < .001) compared with ≤ 100 mg; a history of hypertension (OR, 2.10 [95% CI, 1.54 to 2.72]; P < .001) compared with no hypertension; and serum albumin 2.0 to 3.5 g/dL (OR, 2.21 [95% CI, 1.62 to 3.03]; P < .001) compared with > 3.5 g/dL. The baseline estimated glomerular filtration rate was not significantly associated with the risk of C-AKI. The c-statistics of the score-based model in the DC and the VC were 0.72 (95% CI, 0.69 to 0.75) and 0.70 (95% CI, 0.67 to 0.73), respectively. Scores of 0, 3.5, and 8.5 were associated with a probability of C-AKI of 0.03 (95% CI, 0.03 to 0.05), 0.12 (95% CI, 0.11 to 0.14), and 0.51 (95% CI, 0.43 to 0.60), respectively.ConclusionA score-based model created by using the patient’s age, cisplatin dose, hypertension, and serum albumin is predictive of C-AKI.
Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-09 Catherine M. Bollard; Tamara Tripic; Conrad Russell Cruz; Gianpietro Dotti; Stephen Gottschalk; Vicky Torrano; Olga Dakhova; George Carrum; Carlos A. Ramos; Hao Liu; Meng-Fen Wu; Andrea N. Marcogliese; Cecilia Barese; Youli Zu; Daniel Y. Lee; Owen O’Connor; Adrian P. Gee; Malcolm K. Brenner; Helen E. Heslop; Cliona M. Rooney
Purpose Transforming growth factor-β (TGF-β) production in the tumor microenvironment is a potent and ubiquitous tumor immune evasion mechanism that inhibits the expansion and function of tumor-directed responses; therefore, we conducted a clinical study to discover the effects of the forced expression of a dominant-negative TGF-β receptor type 2 (DNRII) on the safety, survival, and activity of infused tumor-directed T cells. Materials and Methods In a dose escalation study, eight patients with Epstein Barr virus–positive Hodgkin lymphoma received two to 12 doses of between 2 × 107 and 1.5 × 108 cells/m2 of DNRII-expressing T cells with specificity for the Epstein Barr virus–derived tumor antigens, latent membrane protein (LMP)-1 and LMP-2 (DNRII-LSTs). Lymphodepleting chemotherapy was not used before infusion. Results DNRII-LSTs were resistant to otherwise inhibitory concentrations of TGF-β in vitro and retained their tumor antigen–specific activity. After infusion, the signal from transgenic T cells in peripheral blood increased up to 100-fold as measured by quantitative polymerase chain reaction for the transgene, with a corresponding increase in the frequency of functional LMP-specific T cells. Expansion was not associated with any acute or long-term toxicity. DNRII-LSTs persisted for up to ≥ 4 years. Four of the seven evaluable patients with active disease achieved clinical responses that were complete and ongoing in two patients at > 4 years, including in one patient who achieved only a partial response to unmodified tumor-directed T cells. Conclusion TGF-β–resistant tumor-specific T cells safely expand and persist in patients with Hodgkin lymphoma without lymphodepleting chemotherapy before infusion. DNRII-LSTs can induce complete responses even in patients with resistant disease. Expression of DNRII may be useful for the many other tumors that exploit this potent immune evasion mechanism.
Cost Effectiveness of Gene Expression Profile Testing in Community Practice J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-08 Young Chandler; Clyde B. Schechter; Jinani Jayasekera; Aimee Near; Suzanne C. O’Neill; Claudine Isaacs; Charles E. Phelps; G. Thomas Ray; Tracy A. Lieu; Scott Ramsey; Jeanne S. Mandelblatt
PurposeGene expression profile (GEP) testing can support chemotherapy decision making for patients with early-stage, estrogen receptor–positive, human epidermal growth factor 2–negative breast cancers. This study evaluated the cost effectiveness of one GEP test, Oncotype DX (Genomic Health, Redwood City, CA), in community practice with test-eligible patients age 40 to 79 years.MethodsA simulation model compared 25-year societal incremental costs and quality-adjusted life-years (QALYs) of community Oncotype DX use from 2005 to 2012 versus usual care in the pretesting era (2000 to 2004). Inputs included Oncotype DX and chemotherapy data from an integrated health care system and national and published data on Oncotype DX accuracy, chemotherapy effectiveness, utilities, survival and recurrence, and Medicare and patient costs. Sensitivity analyses varied individual parameters; results were also estimated for ideal conditions (ie, 100% testing and adherence to test-suggested treatment, perfect test accuracy, considering test effects on reassurance or worry, and lowest costs).ResultsTwenty-four percent of test-eligible patients had Oncotype DX testing. Testing was higher in younger patients and patients with stage I disease (v stage IIA), and 75.3% and 10.2% of patients with high and low recurrence risk scores received chemotherapy, respectively. The cost-effectiveness ratio for testing (v usual care) was $188,125 per QALY. Considering test effects on worry versus reassurance decreased the cost-effectiveness ratio to $58,431 per QALY. With perfect test accuracy, the cost-effectiveness ratio was $28,947 per QALY, and under ideal conditions, it was $39,496 per QALY.ConclusionGEP testing is likely to have a high cost-effectiveness ratio on the basis of community practice patterns. However, realistic variations in assumptions about key variables could result in GEP testing having cost-effectiveness ratios in the range of other accepted interventions. The differences in cost-effectiveness ratios on the basis of community versus ideal conditions underscore the importance of considering real-world implementation when assessing the new technology.
Cabozantinib, a New Standard of Care for Patients With Advanced Renal Cell Carcinoma and Bone Metastases? Subgroup Analysis of the METEOR Trial J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-08 Bernard Escudier; Thomas Powles; Robert J. Motzer; Thomas Olencki; Osvaldo Arén Frontera; Stephane Oudard; Frederic Rolland; Piotr Tomczak; Daniel Castellano; Leonard J. Appleman; Harry Drabkin; Daniel Vaena; Steven Milwee; Jillian Youkstetter; Julie C. Lougheed; Sergio Bracarda; Toni K. Choueiri
PurposeCabozantinib, an inhibitor of tyrosine kinases including MET, vascular endothelial growth factor receptors, and AXL, increased progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with advanced renal cell carcinoma (RCC) after previous vascular endothelial growth factor receptor–targeted therapy in the phase III METEOR trial. Because bone metastases are associated with increased morbidity in patients with RCC, bone-related outcomes were analyzed in METEOR.Patients and MethodsSix hundred fifty-eight patients were randomly assigned 1:1 to receive 60 mg cabozantinib or 10 mg everolimus. Prespecified subgroup analyses of PFS, OS, and ORR were conducted in patients grouped by baseline bone metastases status per independent radiology committee (IRC). Additional end points included bone scan response per IRC, skeletal-related events, and changes in bone biomarkers.ResultsFor patients with bone metastases at baseline (cabozantinib [n = 77]; everolimus [n = 65]), median PFS was 7.4 months for cabozantinib versus 2.7 months for everolimus (hazard ratio, 0.33 [95% CI, 0.21 to 0.51]). Median OS was also longer with cabozantinib (20.1 months v 12.1 months; hazard ratio, 0.54 [95% CI, 0.34 to 0.84]), and ORR per IRC was higher (17% v 0%). The rate of skeletal-related events was 23% with cabozantinib and 29% with everolimus, and bone scan response per IRC was 20% versus 10%, respectively. PFS, OS, and ORR were also improved with cabozantinib in patients without bone metastases. Changes in bone biomarkers were greater with cabozantinib than with everolimus. The overall safety profiles of cabozantinib and everolimus in patients with bone metastases were consistent with those observed in patients without bone metastases.ConclusionCabozantinib treatment was associated with improved PFS, OS, and ORR when compared with everolimus treatment in patients with advanced RCC and bone metastases and represents a good treatment option for these patients.
Guarantee-Time Bias and Benefits of Surgery for Pleural Mesothelioma J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-05 Steven E. Vogl
We need more information to evaluate the validity of the propensity score matched pairs analysis of surgical treatment of malignant pleural mesothelioma by Nelson et al1 that was based on the National Cancer Database. We need to know how many of the patients had surgery immediately and how many had it deferred. Deferral of surgery whether for collection of multiple opinions or for chemotherapy, radiation, or both (either sequentially or concurrently) would give patients a prolonged survival from diagnosis by virtue of the guarantee time they would have by surviving long enough to reach the time of surgery. Any patients with surgery planned who died during initial chemotherapy or radiation would be counted as nonsurgical patients, and their deaths would be counted as evidence that failure to perform surgery leads to early death. In truth, the early death led to failure to perform surgery. These deaths before they could be counted in the experimental arm gives this arm a guarantee of apparent improved survival.
Optimization of Risk Stratification in Localized Prostate Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-05 Alicia Katherine Morgans
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 67-year-old retired engineering professor was found to have a prostate-specific antigen (PSA) level of 11 ng/mL on a screening test at his annual physical examination. A digital rectal examination revealed a nodule on the right side. He underwent a transrectal ultrasound-guided prostate biopsy that was notable for prostate adenocarcinoma, Gleason 3 + 4 = 7 (Gleason grade group 2; 30% Gleason 4 component) involving two cores (60% and 20% core involvement). A bone scan and pelvic computed tomography scan were negative for evidence of metastatic disease. (Should he undergo prostate magnetic resonance imaging? That seems rather common these days.) He was diagnosed with cT2b intermediate-risk localized prostate cancer (PCa) by National Comprehensive Cancer Network (NCCN) risk group and was seen in the multidisciplinary clinic to discuss management options (Table 1).
Reply to S.E. Vogl J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-05 David B. Nelson; David C. Rice; Jiangong Niu; Reza J. Mehran; Boris Sepesi
We welcome the discussion raised by Vogl1 with regard to our recent article.2 The period of immortality is best described as the duration in which a patient cannot die as a result of operating definitions within a retrospective analysis. This is often a concern with retrospective studies due to the inability to assign patients properly in an intention-to treat fashion. Any surgical patient who did not receive therapy on day 0 was by definition immortal until the date of surgery because a death before surgery would place them in the nonsurgical cohort. This bias also is equally valid for patients who underwent radiation and chemotherapy. The time to surgery was, in fact, brief, with a median of 22 days (interquartile range, 0 to 64 days).
Contemporary Sarcoma Diagnosis, Genetics, and Genomics J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Inga-Marie Schaefer; Gregory M. Cote; Jason L. Hornick
Sarcomas include diverse mesenchymal neoplasms with widely varied prognosis, clinical behavior, and treatment. Owing to their rarity and histologic overlap, accurate diagnosis of sarcomas can be challenging. Our approach has evolved dramatically in the past few decades, where novel insights into the molecular pathogenetic basis for sarcomas has dramatically (re)shaped contemporary diagnosis, building on a largely morphology- and clinical presentation–based strategy. Examples include the introduction of novel immunohistochemical markers that serve as surrogates for molecular genetic alterations and identification of characteristic molecular alterations. Accordingly, cytogenetic and molecular genetic analyses, such as conventional karyotyping, fluorescence in situ hybridization, reverse transcription–polymerase chain reaction, and targeted sequencing, have increasingly been incorporated into the routine diagnostic work-up of these neoplasms. For those sarcomas with complex cytogenetic changes that lack specific alterations, additional testing is often directed toward identifying lines of differentiation and excluding pathognomonic (cyto-)genetic alterations. Although some gene rearrangements are diagnostic of particular sarcoma types, certain fusion partners, most notably EWSR1, are not tumor specific (and may, in fact, also be found in benign tumors). Correlation with clinical, radiologic, morphologic, and immunohistochemical findings is particularly important in tumors with such rearrangements to establish the correct diagnosis, acknowledging the inherent limitations of diagnostic tests. The recognition of sarcomas occurring in cancer predisposition syndromes is critical, with implications not only for the index patient but also potentially for family members, including the need for genetic counseling and sometimes particular types of surveillance. Together, contemporary sarcoma evaluation involves combining the initial morphologic evaluation with diagnostically relevant cytogenetic, molecular, and immunohistochemical testing methods.
Local Control of Soft Tissue and Bone Sarcomas J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Joseph G. Crompton; Koichi Ogura; Nicholas M. Bernthal; Akira Kawai; Fritz C. Eilber
Sarcomas of soft tissue and bone are mesenchymal malignancies that can arise in any anatomic location, most commonly the extremity, retroperitoneum, and trunk. Even for lower grade histologic subtypes, local recurrence can cause significant morbidity and even disease-related death. Although surgery remains the cornerstone of local control, perioperative radiation and systemic therapy are often important adjuvants. This review will summarize the current therapeutic approaches for local control of soft tissue and bone sarcomas.
Perioperative Management of Extremity Soft Tissue Sarcomas J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Rick L. Haas; Alessandro Gronchi; Michiel A.J. van de Sande; Elizabeth H. Baldini; Hans Gelderblom; Christina Messiou; Eva Wardelmann; Axel Le Cesne
Surgery is potentially curative for primary nonmetastatic extremity soft tissue sarcomas. After surgery alone, patients may remain at risk for local recurrences and/or metastatic disease. To reduce the likelihood of a local relapse, the addition of radiotherapy (RT) to limb-sparing surgery may result in higher local control rates of at least 85%. Generally, it can be stated that local control after both preoperative and postoperative RT is comparable, but that preoperative RT comes with a more favorable toxicity profile after prolonged follow-up, albeit at the cost of a higher wound complication rate. Furthermore, recent data suggest that preoperative RT is more cost effective. To reduce the risk of subsequent metastatic disease, systemic chemotherapy can be introduced early during the primary management of these patients. These systemic chemotherapy regimens can also be applied both preoperatively and postoperatively. Finally, with the aim of increasing the antitumor response of perioperative RT, these agents may even be combined with RT, concurrently and sequentially. While designing new preoperative combination regimens, responses should be carefully monitored by both sophisticated radiologic and pathologic evaluations. This article reviews all these aspects, in addition to limb-sparing surgery.
Emerging Targeted and Immune-Based Therapies in Sarcoma J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Seth M. Pollack; Matthew Ingham; Matthew B. Spraker; Gary K. Schwartz
Soft tissue and bone sarcomas are malignancies of mesenchymal origin, and more than 50 subtypes are defined. For most sarcomas, locally advanced or unresectable disease is still treated with cytotoxic chemotherapy. Recently, our understanding of subtype-specific cancer biology has expanded, and it has revealed distinct molecular alterations responsible for tumor initiation and progression. These findings have motivated the development of targeted therapies that are being evaluated in subtype-specific or biomarker-driven clinical trials. Indeed, the spectrum of targeted drug development in sarcoma now spans many of the most active paradigms in cancer research and includes agents that target cancer-related vulnerabilities in receptor tyrosine kinases and intracellular signaling pathways, epigenetics, metabolism, nuclear-cytoplasmic transport, and many others. Our understanding of the sarcoma immune microenvironment and heterogeneous mechanisms of tumor immune evasion has also expanded. Although a subset of sarcomas appears inflamed and responsive to immune checkpoint blockade with programmed death 1 (PD-1) targeted agents, novel immunotherapies and combinations likely will be needed for most subtypes. A variety of approaches—including targeting immune checkpoints other than PD-1; modulating tumor-associated macrophage phenotype from tumor-promoting to tumor-suppressive status; using cellular-based therapies, such as chimeric antigen and high-affinity T-cell receptors to deepen the adaptive immune response; and reinvigorating older approaches, such as vaccines and oncolytic virus-based treatments—are being investigated. The goal of these new approaches is to harness subtype-specific insights into cancer and immune biology to bring more effective and less toxic treatments to the clinic for the benefit of patients with sarcoma.
Gastrointestinal Stromal Tumors J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Margaret von Mehren; Heikki Joensuu
GI stromal tumors (GISTs) are neoplasms with a varying malignancy potential ranging from virtually indolent tumors to rapidly progressing cancers. GISTs occur throughout the intestinal tract, and most harbor an activating mutation in either KIT or platelet-derived growth factor A (PDGFRA). Diagnosis is made using immunohistochemistry, but molecular testing with mutation analysis is paramount for selection of appropriate therapy. Most small GISTs are cured with surgery. Tyrosine kinase inhibitor (TKI) therapy has led to substantial improvements in survival, both for patients with localized GIST and those with advanced disease. Adjuvant therapy with imatinib benefits patients with a high risk of recurrence, with studies suggesting most benefit with at least 3 years of therapy. Neoadjuvant imatinib therapy should be considered for patients requiring extensive surgery, aiming at shrinking the tumor to allow organ preservation and less extensive surgery. The following three TKIs have been approved for the management of advanced disease: imatinib, sunitinib, and regorafenib; imatinib is usually the best tolerated of the three and the standard first-line treatment. TKIs benefit the majority of patients with advanced GIST but have no or limited efficacy in patients with the PDGFRA D842V mutation or patients with GIST lacking KIT and PDGFRA mutations. Surgery, the mainstay of primary tumor management, also plays a role in the advanced disease setting for selected patients, as do some other approaches such as palliative radiation therapy. Research continues to identify novel therapies, in particular effective agents to treat TKI-refractory disease.
Soft Tissue and Uterine Leiomyosarcoma J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Suzanne George; César Serrano; Martee L. Hensley; Isabelle Ray-Coquard
Leiomyosarcoma (LMS) is one of the most common subtypes of soft tissue sarcoma in adults and can occur in almost any part of the body. Uterine leiomyosarcoma is the most common subtype of uterine sarcoma. Increased awareness of this unique histology has allowed for the development of drugs that are specific to LMS and has begun to shed light on the similarities and possible unique aspects of soft tissue and uterine LMS. In this review, we summarize the current understanding of the epidemiology, diagnosis, genomics, and treatment options for LMS.
Clinical and Molecular Spectrum of Liposarcoma J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Alex Thomas John Lee; Khin Thway; Paul H. Huang; Robin Lewis Jones
Liposarcomas are rare malignant tumors of adipocytic differentiation. The classification of liposarcomas into four principal subtypes reflects the distinct clinical behavior, treatment sensitivity, and underlying biology encompassed by these diseases. Increasingly, clinical management decisions and the development of investigational therapeutics are informed by an improved understanding of subtype-specific molecular pathology. Well-differentiated liposarcoma is the most common subtype and is associated with indolent behavior, local recurrence, and insensitivity to radiotherapy and chemotherapy. Dedifferentiated liposarcoma represents focal progression of well-differentiated disease into a more aggressive, metastasizing, and fatal malignancy. Both of these subtypes are characterized by recurrent amplifications within chromosome 12, resulting in the overexpression of disease-driving genes that have been the focus of therapeutic targeting. Myxoid liposarcoma is characterized by a pathognomonic chromosomal translocation that results in an oncogenic fusion protein, whereas pleomorphic liposarcoma is a karyotypically complex and especially poor-prognosis subtype that accounts for less than 10% of liposarcoma diagnoses. A range of novel pharmaceutical agents that aim to target liposarcoma-specific biology are under active investigation and offer hope of adding to the limited available treatment options for recurrent or inoperable disease.
Biology and Management of Undifferentiated Pleomorphic Sarcoma, Myxofibrosarcoma, and Malignant Peripheral Nerve Sheath Tumors: State of the Art and Perspectives J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Brigitte C. Widemann; Antoine Italiano
Undifferentiated pleomorphic sarcomas, myxofibrosarcomas, and malignant peripheral nerve sheath tumors are characterized by complex genomic characteristics and aggressive clinical behavior. Recent advances in the understanding of the pathogenesis of these tumors may allow for the development of more-effective innovative therapeutic strategies, including immunotherapies. This review describes the current knowledge of the epidemiology, clinical presentation, treatment, and pathogenesis of these tumors and highlights ongoing and future research.
Rhabdomyosarcoma, Ewing Sarcoma, and Other Round Cell Sarcomas J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Alberto S. Pappo; Uta Dirksen
Several recent advances have been made in the diagnosis and therapy of malignant small round cell tumors that affect children, particularly in rhabdomyosarcoma, Ewing sarcoma, and other round cell sarcomas. These advances have provided new insights into the pathologic, histologic, and genomic characterization of specific tumor subtypes, which has led to the identification of novel therapeutic targets and improved stratification of risk. This has, in turn, led to improved efficacy in clinical trials of new drug combinations, thereby increasing the survival of patients with newly diagnosed and refractory or recurrent round cell sarcomas. Here, we review the progress that has been made using genomics to identify novel pathologic genomic rearrangements, as well as therapeutic targets. We also describe how clinical and molecular factors have helped refine risk stratification and therapies that have led to improved clinical outcomes in patients with round cell sarcomas.
Synovial Sarcoma: Current Concepts and Future Perspectives J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Silvia Stacchiotti; Brian Andrew Van Tine
Synovial sarcoma (SS) is a rare sarcoma driven by a translocation between SS18 and SSX 1, 2, or 4. With approximately 800 to 1,000 cases a year in the United States, it most commonly affects young adults between the ages of 15 and 30 years. The resultant tumors are either monophasic (pure sarcomas), biphasic (a combination or epithelioid and sarcomatous components), or poorly differentiated. The hybrid transcription factor SS18:SSX alters SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling and global methylation patterns that may allow for future therapeutic opportunities. In this review, we focus on the pharmacologic management of SS, both in the curative setting, where the standard approach is wide surgical excision combined with radiotherapy and/or (neo)adjuvant chemotherapy as appropriate, and in the palliative setting. In advanced disease, chemotherapy with anthracyclines and/or ifosfamide, trabectedin, or pazopanib has been demonstrated to be more active compared with other soft tissue sarcomas. In addition, a better understanding of the molecular and immunologic characteristics of SS has allowed for the identification of new potential targets and the development of novel biology-driven therapies that are all at different stages of testing. There include targeted agents, immunotherapy, and metabolic therapies. Because the impact of these strategies for improving SS outcome is still limited, current and future research is strongly needed to better understand the tumor biology, to identify predictive biomarkers, and to improve the outcomes for patients with SS.
Osteosarcoma, Chondrosarcoma, and Chordoma J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Jeremy S. Whelan; Lara E. Davis
Osteosarcoma (OS), chondrosarcoma, and chordoma are characterized by multiple challenges to the investigator, clinician, and patient. One consequence of their rarity among sarcomas, as well as their biologic and clinical heterogeneity, is that management guidelines are inadequate to inform the range of individual patient-treatment decisions from diagnosis, approaches to surgery, chemotherapy, radiotherapy, treatment of recurrence, palliative care, and quality of survivorship. Of high-grade sarcomas, OSs are among the most curable, with more than two-thirds of patients with localized disease likely to achieve long-term survival. Neoadjuvant chemotherapy comprising cisplatin, doxorubicin, and methotrexate with intercalated surgery is the standard of care for resectable OS in those younger than 40 years. Outcomes for OS presenting with unresectable metastases or recurrent disease, or in those older than 40 years are generally poor. Overall results have improved little for all patients with OS, and new treatments are needed. Surgical resection remains the cornerstone of management for chondrosarcoma and chordoma. However, the application of new biologic insights to therapeutic development indicates that improved treatments may soon be routine for patients with chondrosarcoma and chordoma for whom surgery alone is inadequate. For all these uncommon diseases, patients should be offered specialist expert care delivered by experienced multidisciplinary teams in high-volume centers.
Pathologic Angiogenesis of Malignant Vascular Sarcomas: Implications for Treatment J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Jalal A. Khan; Robert G. Maki; Vinod Ravi
Angiosarcoma, epithelioid hemangioendothelioma, and Kaposi sarcoma are classified according to the line of differentiation that these neoplastic cells most closely resemble: the endothelial cell. Although these malignant vascular sarcomas demonstrate immunohistochemical and ultrastructural features typical of this lineage, they vary dramatically in presentation and behavior, reflecting oncologic mechanisms unique to each. Antineoplastic therapies offer significant benefit, but because of the rarity of these cancers, novel therapies are slow to develop, and treatment options for these cancers remain limited. Antiangiogenic approaches that have shown benefit in other malignancies have not fully realized their promise in vascular tumors, suggesting that these tumors do not depend entirely on either angiogenic growth factors or on neighboring endothelia that are affected by these agents. Nonetheless, translational studies have begun to unravel these distinct pathologies, identifying novel translocation products, targets of oncogenic virulence factors, and genomic mutations that hijack angiogenic signaling and drive malignant growth. Concurrently, an elaborate and highly regulated model of angiogenesis and lymphangiogenesis involving vascular endothelial growth factor–receptor tyrosine kinase and TGF-β and Notch pathways has emerged that informs treatment of these tumors as well as cancer in general. This review summarizes the literature on malignant vascular sarcomas in the context of current models of angiogenesis and, in light of recent clinical trial data, could help clinician-scientists generate novel therapeutic approaches.
Locally Aggressive Connective Tissue Tumors J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Mrinal M. Gounder; David M. Thomas; William D. Tap
In this review, we highlight the complexities of the natural history, biology, and clinical management of three intermediate connective tissue tumors: desmoid tumor (DT) or aggressive fibromatosis, tenosynovial giant cell tumor (TGCT) or diffuse-type pigmented villonodular synovitis (dtPVNS), and giant cell tumor of bone (GCTB). Intermediate histologies include tumors of both soft tissue and bone origin and are locally aggressive and rarely metastatic. Some common aspects to these tumors are that they can be locally infiltrative and/or impinge on critical organs, which leads to disfigurement, pain, loss of function and mobility, neurovascular compromise, and occasionally life-threatening consequences, such as mesenteric, bowel, ureteral, and/or bladder obstruction. DT, PVNS, and GCTB have few and recurrent molecular aberrations but, paradoxically, can have variable natural histories. A multidisciplinary approach is recommended for optimal management. In DT and PVNS, a course of observation may be appropriate, and any intervention should be guided by symptoms and/or disease progression. A surgical approach should take into consideration the infiltrative nature, difficulty in obtaining wide margins, high recurrence rates, acute and chronic surgical morbidities, and impact on quality of life. There are similar concerns with radiation, which especially relate to optimal field and transformation to high-grade radiation-associated sarcomas. Systemic therapies must be considered carefully in light of acute and chronic toxicities. Although standard and novel therapies are promising, many unanswered questions, such as duration of therapy and optimal end points to evaluate efficacy of drugs in clinical practice and trials, exist. Predictive biomarkers and novel clinical trial end points, such as volumetric measurement, magnetic resonance imaging T2 weighted mapping, nuclear imaging, and patient-reported outcomes, are in development and will require validation in prospective trials.
Carcinosarcomas and Related Cancers: Tumors Caught in the Act of Epithelial-Mesenchymal Transition J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-10 Angela Pang; Mariana Carbini; Andre L. Moreira; Robert G. Maki
In this review, we outline the biology and management of patients with carcinosarcomas and related malignancies, which are often included under the broader concept of sarcomatoid carcinomas. Carcinosarcomas are unusual tumors that are commonly gynecologic in origin, where they are referred to as malignant mixed Müllerian tumors, but may appear in any anatomic site. Although a variety of hypotheses have been presented as to the biphasic nature of these tumors, carcinosarcomas seem to represent the best example in human cancers of the concept of epithelial-mesenchymal transition (EMT), in which the two parts of the tumor are genomically related to one another, as opposed to the mesenchymal component that represents a second neoplasm or (benign) reactive process. In general, patients with carcinosarcomas fare worse than patients with carcinomas of the same anatomic site. Treatment paradigms for carcinosarcomas generally follow those of carcinomas of the same organ site, except where clinical trials provide more specific options. Agents that block or reverse EMT are worth examination in patients with carcinosarcoma and arguably may be even more effective in carcinomas, given evidence of dependence on EMT to generate successful metastases. Information about EMT may also inform other phase transitions in cancer, such as those between prostate or lung carcinoma and more aggressive tumors with neuroendocrine differentiation.
TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-04 Maoxiang Qian; Xueyuan Cao; Meenakshi Devidas; Wenjian Yang; Cheng Cheng; Yunfeng Dai; Andrew Carroll; Nyla A. Heerema; Hui Zhang; Takaya Moriyama; Julie M. Gastier-Foster; Heng Xu; Elizabeth Raetz; Eric Larsen; Naomi Winick; W. Paul Bowman; Paul L. Martin; Elaine R. Mardis; Robert Fulton; Gerard Zambetti; Michael Borowitz; Brent Wood; Kim E. Nichols; William L. Carroll; Ching-Hon Pui; Charles G. Mullighan; William E. Evans; Stephen P. Hunger; Mary V. Relling; Mignon L. Loh; Jun J. Yang
Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li-Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children’s Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0%) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P < .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P < .001) and were more likely to have hypodiploid ALL (65.4% v 1.2%; P < .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P < .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1% and 0.7% (P < .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.
Association of Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations With Survival in Metastatic Triple-Negative Breast Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-03 Daniel G. Stover; Heather A. Parsons; Gavin Ha; Samuel S. Freeman; William T. Barry; Hao Guo; Atish D. Choudhury; Gregory Gydush; Sarah C. Reed; Justin Rhoades; Denisse Rotem; Melissa E. Hughes; Deborah A. Dillon; Ann H. Partridge; Nikhil Wagle; Ian E. Krop; Gad Getz; Todd R. Golub; J. Christopher Love; Eric P. Winer; Sara M. Tolaney; Nancy U. Lin; Viktor A. Adalsteinsson
Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.
Circulating Tumor DNA Guides Prognosis in Metastatic Triple-Negative Breast Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-03 Andjelija Zivanovic Bujak; Sarah-Jane Dawson
Triple-negative breast cancer (TNBC) constitutes up to 15% of all breast cancers but accounts for > 25% of breast cancer–related deaths, with limited improvements in overall survival over the past 20 years.1-3 It is a diagnosis of exclusion, defined by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), and is consequently accompanied by a lack of targeted therapeutic options. TNBC tumors frequently have inferior clinical outcomes and are biologically more aggressive than other breast cancer subtypes, with chemotherapy remaining the therapy of choice.1-3 Although diagnosed as a single tumor entity, there is a high degree of molecular heterogeneity within TNBC. Several attempts have been made to subdivide TNBC into clinically relevant subgroups, and there is early clinical evidence of a differential response to therapy depending on the underlying molecular features.4-9 Emerging clinical trials of targeted agents offer glimpses of hope, including the use of poly ADP ribose polymerase inhibitors in TNBCs with DNA repair defects,10,11 antiandrogen therapy in patients who are androgen receptor positive,12 and phosphatidylinositol 3-kinase inhibitors, which may sensitize BRCA-proficient TNBCs to poly ADP ribose polymerase inhibition.13 Moreover, a subset of TNBCs seems to be immunogenic, with high levels of tumor-infiltrating lymphocytes, providing a strong rationale for ongoing efforts to explore the role of immunotherapies.14,15 Improved understanding of the molecular heterogeneity of TNBC and the relevant pathways involved will undoubtedly hold the key to better outcomes for patients with this disease.
Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non–Small-Cell Lung Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-02 Zhongxing Liao; J. Jack Lee; Ritsuko Komaki; Daniel R. Gomez; Michael S. O’Reilly; Frank V. Fossella; George R. Blumenschein Jr; John V. Heymach; Ara A. Vaporciyan; Stephen G. Swisher; Pamela K. Allen; Noah Chan Choi; Thomas F. DeLaney; Stephen M. Hahn; James D. Cox; Charles S. Lu; Radhe Mohan
Purpose This randomized trial compared outcomes of passive scattering proton therapy (PSPT) versus intensity-modulated (photon) radiotherapy (IMRT), both with concurrent chemotherapy, for inoperable non–small-cell lung cancer (NSCLC). We hypothesized that PSPT exposes less lung tissue to radiation than IMRT and thereby reduces toxicity without compromising tumor control. The primary end points were grade ≥ 3 radiation pneumonitis (RP) and local failure (LF). Patients and Methods Eligible patients had stage IIB to IIIB NSCLC (or stage IV NSCLC with a single brain metastasis or recurrent lung or mediastinal disease after surgery) who were candidates for concurrent chemoradiation therapy. Pairs of treatment plans for IMRT and PSPT were created for each patient. Patients were eligible for random assignment only if both plans satisfied the same prespecified dose-volume constraints for at-risk organs at the same tumor dose. Results Compared with IMRT (n = 92), PSPT (n = 57) exposed less lung tissue to doses of 5 to 10 Gy(RBE), which is the absorbed Gy dose multiplied by the relative biologic effectiveness (RBE) factor for protons; exposed more lung tissue was exposed to $ 20 Gy(RBE), but exposed less heart tissue at all dose levels between 5 and 80 Gy(RBE). The grade $ 3 RP rate for all patients was 8.1% (IMRT, 6.5%; PSPT, 10.5%); corresponding LF rates were 10.7% (all), 10.9% (IMRT), and 10.5% (PSPT). The posterior probability of IMRT being better than PSPT was 0.54. Exploratory analysis showed that the RP and LF rates at 12 months for patients enrolled before versus after the trial midpoint were 21.1% (before) versus 18.2% (after) for the IMRT group (P = .047) and 31.0% (before) versus 13.1% (after) for the PSPT group (P = .027). Conclusion PSPT did not improve dose-volume indices for lung but did for heart. No benefit was noted in RP or LF after PSPT. Improvements in both end points were observed over the course of the trial.
Population-Based Genetic Testing for BRCA1 and BRCA2 J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-02 Steven Narod; Mohammad R. Akbari
In an editorial in a recent issue of Journal of Clinical Oncology, Kevin Hughes1 provides the rationale for expanding genetic testing for BRCA1 and BRCA2 to a much greater number of women than are currently eligible and discusses the potential benefit of introducing population-based genetic testing. The editorial is a commentary on the article by Childers et al,2 who provide data to show that, among women in North America with a BRCA1 or BRCA2 mutation, only a small proportion are currently being tested and that we have failed to achieve the potential for cancer prevention through genetic medicine. This is in large part a result of systemic barriers in place, such as an elaborate referral and triage mechanism required for test approval if third-party reimbursement is to be obtained. In particular, the requirement of in-person pretest genetic counseling is restrictive. The argument for widespread testing made by Hughes1 is convincing to us, and we at Women’s College Hospital introduced in 2017 a population-based genetic testing program for all Canadians older than age 18 years, regardless of personal or family history of cancer. We have previously conducted trials of population-based testing in Jewish women3 and in Polish women,4 but we now offer the testing unrestricted throughout Canada. The Screen Project offers Internet-based genetic testing using a shipped saliva specimen in collaboration with Veritas Genetics (Danvers, MA).5 We have deliberately chosen to restrict testing to BRCA1 and BRCA2 because it is relatively easy to distinguish a deleterious mutation from a variant of unknown significance for these two genes and there is wealth of evidence to support personalized management in the preventive and treatment arenas. The cost of the test is US $165 and frees our client from the burden of seeking reimbursement. Pretest counseling is Web-based, but each carrier identified is informed by our genetic counselor and is offered an in-person counseling session in Toronto or locally (we call this the guided direct-to-consumer approach). We are concerned that by making multigene panel testing the standard of care, counselors will be inundated with requests to interpret variants of uncertain significance for genes not well studied and we will lose sight of the goal of offering a test that provides meaningful and clear data and that can be used to lessen the burden of cancer in Canada.
Genetic Testing: Multiple Problems to Solve J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-02 Erica Ramos; Joy Larsen Haidle
We read with interest the editorial by Kevin Hughes1 and suggest several points worth highlighting. At its core, the question of “What problem are we trying to solve?” presents a false dichotomy.
Adaptation of Genetic Counseling According to an Individual’s Literacy Regarding Genomics J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-02 Sho Nakamura; Hiroto Narimatsu
Childers et al1 revealed that only 25.0% of patients with breast and ovarian cancer who met five of the 16 National Comprehensive Cancer Network criteria for BRCA1/2 testing had discussions with health care providers about it and that only 13.8% had been tested. We have indicated that literacy related to genomics (genomic literacy)—that is, individuals’ knowledge and understanding about genetics and genomics—is essential in applying genomic information to clinical practices.2 Notably, genomic literacy will be important for future clinical applications of genomic information, as more genes and their mutations are researched.
Reply to E. Ramos et al J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-02 Kevin S. Hughes
In my editorial in Journal of Clinical Oncology,1 I asked about which genetic testing problem we are trying to solve. Is it that “large numbers of women have had undue levels of stress and anxiety, have not received proper informed consent, or have been managed inappropriately because they were tested by someone other than a genetic counselor” or that “hundreds of thousands of mutation carriers are still unaware of their status and will develop cancers that could have been prevented or found earlier”?
Reply to S. Nakamura et al and S. Narod et al J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-02 Christopher P. Childers; Kimberly K. Childers; Melinda Maggard-Gibbons; James Macinko
We thank Nakamura and Narimatsu1 and Narod and Akbari2 for their interest in our work. In brief, our study found that less than one in five women with a history of breast or ovarian cancer who met select National Comprehensive Cancer Network criteria have undergone genetic testing.3 This translates to more than one million women who do not have vital information that may guide cancer treatment, prevention, and screening strategies for them and their family members. Perhaps more interesting and nuanced is the finding that 75% of these eligible women had never even discussed testing with a health care provider. The identification of high-risk patients remains a preeminent challenge in cancer genetic testing.
Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma J. Clin. Oncol. (IF 24.008) Pub Date : 2017-12-28 Caroline Robert; Antoni Ribas; Omid Hamid; Adil Daud; Jedd D. Wolchok; Anthony M. Joshua; Wen-Jen Hwu; Jeffrey S. Weber; Tara C. Gangadhar; Richard W. Joseph; Roxana Dronca; Amita Patnaik; Hassane Zarour; Richard Kefford; Peter Hersey; Jin Zhang; James Anderson; Scott J. Diede; Scot Ebbinghaus; F. Stephen Hodi
Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study (ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.
Smoking, B Vitamins, and Lung Cancer: The Chicken or the Egg Causality Dilemma J. Clin. Oncol. (IF 24.008) Pub Date : 2017-12-28 Rima Obeid; Klaus Pietrzik
A recent article by Brasky et al1 about the Vitamins and Lifestyle (VITAL) study reported a seemingly logical association between lung cancer and the use of multivitamins that contain vitamin B12 > 55 µg/d or B6 > 20 mg/d. There is no concise hypothesis on a critical exposure dose, duration, time window, or combinations of vitamins that could cause future lung cancer in smokers. Smoking start, duration, and intensity, and previous morbidities in smokers can prompt individuals to take supplements, and this point needs careful assessment. We argue that being at risk for cancer has resulted in individuals taking multivitamins and has increased the future risk of lung cancer at the same time (multivitamins ← being at risk → lung cancer). The following facts support our argument.
Reply to R. Obeid et al J. Clin. Oncol. (IF 24.008) Pub Date : 2017-12-28 Theodore M. Brasky; Emily White; Chi-Ling Chen
We thank Obeid and Pietrzik1 for their letter concerning our recent article.2 The authors make a number of points to explain how our results reflect reverse causation—that participants in the Vitamins and Lifestyle (VITAL) study were at greater risk for developing cancer (or lung cancer, specifically) and therefore began using supplements. We hope that our response is instructive.
Advancing the Science of Cancer Health Disparities Research J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-01 Lauren P. Wallner; Jennifer J. Griggs
It is not news that significant disparities in cancer-related outcomes exist across race and ethnicity. There is a wealth of literature to document disparate care, particularly with respect to black versus white disparities in cancer survival.1,2 Disparities in cancer-specific survival go beyond just race/ethnicity, however, and include differences across sociodemographic characteristics, including individual socioeconomic position (education, income),2 insurance status,3 neighborhood socioeconomic status (SES),4,5 and marital status.6 In addition, it is well established that differences in clinical factors contribute to the disparities seen in survival after cancer, including varying tumor characteristics at diagnosis, differences in treatment, access to health care, and health-seeking behaviors.7
Integrated Risk Stratification Using Minimal Residual Disease and Sentinel Genetic Alterations in Pediatric Acute Lymphoblastic Leukemia J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-01 Stephen P. Hunger
Treatment of pediatric acute lymphoblastic leukemia (ALL) has provided a paradigm for cancer therapy since 1948, when Farber and Diamond1 first demonstrated that chemotherapy could induce remission in human cancer. Once curative therapies for ALL were developed, age and WBC count at diagnosis were identified as important prognostic factors that were predictive of response and outcome.2 It was later found that early response to therapy—as measured by morphologic clearance of blasts from the blood or marrow during induction therapy—was a strong predictor of outcome.3,4 It is now recognized that detection of minimal residual disease (MRD) by either PCR amplification of clonotypic IG/TCR gene rearrangements or flow cytometric detection of leukemia-associated phenotypes is perhaps the strongest predictor of event-free survival (EFS) and overall survival (OS).5-7 The presence of specific recurrent sentinel genetic lesions in leukemia cells is also a powerful prognostic factor.8 There is general agreement, not universal, that good risk factors include ETV6-RUNX1 fusion and high hyperdiploidy and/or favorable chromosome trisomies, whereas poor risk factors include BCR-ABL1 fusion, KMT2A (MLL) gene fusions, intrachromosomal amplification of chromosome 21 (iAMP21), and hypodiploidy.
Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-01 Vivek Subbiah; Robert J. Kreitman; Zev A. Wainberg; Jae Yong Cho; Jan H.M. Schellens; Jean Charles Soria; Patrick Y. Wen; Christoph Zielinski; Maria E. Cabanillas; Gladys Urbanowitz; Bijoyesh Mookerjee; Dazhe Wang; Fatima Rangwala; Bhumsuk Keam
Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E–mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E–mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E–mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.
Factors That Contributed to Black-White Disparities in Survival Among Nonelderly Women With Breast Cancer Between 2004 and 2013 J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-01 Ahmedin Jemal; Anthony S. Robbins; Chun Chieh Lin; W. Dana Flanders; Carol E. DeSantis; Elizabeth M. Ward; Rachel A. Freedman
Purpose To estimate the contribution of differences in demographics, comorbidity, insurance, tumor characteristics, and treatment to the overall mortality disparity between nonelderly black and white women diagnosed with early-stage breast cancer. Patients and Methods Excess relative risk of all-cause death in black versus white women diagnosed with stage I to III breast cancer, expressed as a percentage and stratified by hormone receptor status for each variable (demographics, comorbidity, insurance, tumor characteristics, and treatment) in sequentially, propensity-scored, optimally matched patients by using multivariable hazard ratios (HRs). Results We identified 563,497 white and black women 18 to 64 years of age diagnosed with stage I to III breast cancer from 2004 to 2013 in the National Cancer Data Base. Among women with hormone receptor–positive disease, who represented 78.5% of all patients, the HR for death in black versus white women in the demographics-matched model was 2.05 (95% CI, 1.94 to 2.17). The HR decreased to 1.93 (95% CI, 1.83 to 2.04), 1.54 (95% CI, 1.47 to 1.62), 1.30 (95% CI, 1.24 to 1.36), and 1.25 (95% CI, 1.19 to 1.31) when sequentially matched for comorbidity, insurance, tumor characteristics, and treatment, respectively. These factors combined accounted for 76.3% of the total excess risk of death in black patients; insurance accounted for 37.0% of the total excess, followed by tumor characteristics (23.2%), comorbidities (11.3%), and treatment (4.8%). Results generally were similar among women with hormone receptor–negative disease, although the HRs were substantially smaller. Conclusion Matching by insurance explained one third of the excess risk of death among nonelderly black versus white women diagnosed with early-stage breast cancer; matching by tumor characteristics explained approximately one fifth of the excess risk. Efforts to focus on equalization of access to care could substantially reduce ethnic/racial disparities in overall survival among nonelderly women diagnosed with breast cancer.
Racial and Ethnic Disparities in Cancer Survival: The Contribution of Tumor, Sociodemographic, Institutional, and Neighborhood Characteristics J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-01 Libby Ellis; Alison J. Canchola; David Spiegel; Uri Ladabaum; Robert Haile; Scarlett Lin Gomez
Purpose Racial/ethnic disparities in cancer survival in the United States are well documented, but the underlying causes are not well understood. We quantified the contribution of tumor, treatment, hospital, sociodemographic, and neighborhood factors to racial/ethnic survival disparities in California. Materials and Methods California Cancer Registry data were used to estimate population-based cancer-specific survival for patients diagnosed with breast, prostate, colorectal, or lung cancer between 2000 and 2013 for each racial/ethnic group (non-Hispanic black, Hispanic, Asian American and Pacific Islander, and separately each for Chinese, Japanese, and Filipino) compared with non-Hispanic whites. The percentage contribution of factors to overall racial/ethnic survival disparities was estimated from a sequence of multivariable Cox proportional hazards models. Results In baseline models, black patients had the lowest survival for all cancer sites, and Asian American and Pacific Islander patients had the highest, compared with whites. Mediation analyses suggested that stage at diagnosis had the greatest influence on overall racial/ethnic survival disparities accounting for 24% of disparities in breast cancer, 24% in prostate cancer, and 16% to 30% in colorectal cancer. Neighborhood socioeconomic status was an important factor in all cancers, but only for black and Hispanic patients. The influence of marital status on racial/ethnic disparities was stronger in men than in women. Adjustment for all covariables explained approximately half of the overall survival disparities in breast, prostate, and colorectal cancer, but it explained only 15% to 40% of disparities in lung cancer. Conclusion Overall reductions in racial/ethnic survival disparities were driven largely by reductions for black compared with white patients. Stage at diagnosis had the largest effect on racial/ethnic survival disparities, but earlier detection would not entirely eliminate them. The influences of neighborhood socioeconomic status and marital status suggest that social determinants, support mechanisms, and access to health care are important contributing factors.
Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia J. Clin. Oncol. (IF 24.008) Pub Date : 2018-01-01 David O’Connor; Amir Enshaei; Jack Bartram; Jeremy Hancock; Christine J. Harrison; Rachael Hough; Sujith Samarasinghe; Claire Schwab; Ajay Vora; Rachel Wade; John Moppett; Anthony V. Moorman; Nick Goulden
Purpose Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. Patients and Methods We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. Results MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different (P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype–specific MRD values allowed more refined risk group stratification. Conclusion A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse.
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