A Phase 3 Biomarker Validation of GALAD for the Detection of Hepatocellular Carcinoma in Cirrhosis.

BACKGROUND & AIMS: Better surveillance tests for hepatocellular carcinoma (HCC) are needed. The GALAD score [Gender, Age, AFP-L3, AFP, and Des-carboxy-prothrombin] has been shown to have excellent sensitivity and specificity for HCC in phase two studies. We performed a phase three biomarker validation study to compare GALAD with AFP in detecting HCC. METHODS: This is a prospective study of patients with cirrhosis enrolled at seven centers. Surveillance for HCC was performed every 6 months at each site, and HCC diagnosis was confirmed per AASLD guidelines. Blood for biomarker research was obtained at each follow-up visit and stored in a biorepository. Measurements of AFP, AFP-L3, and DCP (des-gamma carboxyprothrombin) were performed in a FujiFilm laboratory by staff blinded to clinical data. The performance of GALAD in detecting HCC was retrospectively evaluated within 12 months prior to the clinical diagnosis. All analyses were conducted by an unblinded statistician in the EDRN data management and coordinating center. RESULTS: A total of 1,558 patients with cirrhosis were enrolled and followed for a median of 2.2 years. A total of 109 patients developed HCC (76 very early or early stage) with an annual incident rate of 2.4%. The AUC for AFP and GALAD within 12 months prior to HCC 0.66 and 0.78 (p<0.001), respectively. Using cutoff for GALAD of -1.36, the specificity was 82% and sensitivity at 12 months prior to HCC diagnosis was 62%. For comparison, performance of AFP at 82% specificity showed 41% sensitivity at 12 months prior to HCC diagnosis (p=0.001). CONCLUSION: GALAD score, compared to AFP, improves the detection of HCC within 12 months prior to the actual diagnosis.

HES V2.0 outperforms GALAD for detection of HCC: A phase 3 biomarker study in the United States.

BACKGROUND AND AIMS: The original hepatocellular carcinoma early detection screening (HES) score, which combines alpha-fetoprotein (AFP) with age, alanine aminotransferase, and platelets, has better performance than AFP alone for early HCC detection. We have developed HES V2.0 by adding AFP-L3 and des-gamma-carboxy prothrombin to the score and compared its performance to GALAD and ASAP scores among patients with cirrhosis. APPROACH AND RESULTS: We conducted a prospective-specimen collection, retrospective-blinded-evaluation phase 3 biomarker cohort study in patients with cirrhosis enrolled in imaging and AFP surveillance. True-positive rate (TPR)/sensitivity and false-positive rate for any or early HCC were calculated for GALAD, ASAP, and HES V2.0 scores within 6, 12, and 24 months of HCC diagnosis. We calculated the AUROC curve and estimated TPR based on an optimal threshold at a fixed false-positive rate of 10%. We analyzed 2331 patients, of whom 125 developed HCC (71% in the early stages). For any HCC, HES V2.0 had higher TPR than GALAD overall (+7.2%), at 6 months (+3.6%), at 12 months (+7.2%), and 24 months (+13.0%) before HCC diagnosis. HES V2.0 had higher TPR than ASAP for all time points (+5.9% to +12.0%). For early HCC, HES V2.0 had higher sensitivity/TPR than GALAD overall (+6.7%), at 12 months (+6.3%), and 24 months (+14.6%) but not at 6 months (+0.0%) and higher than ASAP for all time points (+13.4% to +18.0%). CONCLUSIONS: In a prospective cohort study, HES V2.0 had a significantly higher performance for identifying new HCC, including early stage, than GALAD or ASAP.

A randomized phase II study of metronomic cyclophosphamide and methotrexate (CM) with or without bevacizumab in patients with advanced breast cancer.

PURPOSE: Metronomic chemotherapy has the potential to offer tumor control with reduced toxicity when compared to standard dose chemotherapy in patients with metastatic breast cancer. As metronomic chemotherapy may target the tumor microvasculature, it has the potential for synergistic effects with antiangiogenic agents such as the VEGF-A inhibitor bevacizumab. METHODS: In this randomized phase II study, patients with metastatic breast cancer were randomized to receive metronomic oral cyclophosphamide and methotrexate (CM) combined with bevacizumab (Arm A) or CM alone (Arm B). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: A total of 55 patients were enrolled, with 34 patients treated on Arm A and 21 patients treated on Arm B. The ORR was modestly higher in Arm A (26%) than in Arm B (10%); neither met the 40% cutoff for further clinical evaluation. The median time to progression (TTP) was 5.52 months (3.22-13.6) on Arm A and 1.82 months (1.54-6.70) on Arm B (log-rank p = 0.008). The median OS was 29.6 months (17.2-NA) on Arm A and 16.2 months (15.7-NA) on Arm B (log-rank p = 0.7). Common all-grade adverse events in both arms included nausea, fatigue, and elevated AST. CONCLUSION: The combination of metronomic CM with bevacizumab significantly improved PFS over CM alone, although there was no significant difference in OS. Oral metronomic chemotherapy alone has limited activity in advanced breast cancer. CLINICALTRIALS: gov Identifier: NCT00083031. Date of Registration: May 17, 2004.

Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial.

BACKGROUND: We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis. METHODS: In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m2) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual. FINDINGS: Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1-11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3-94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3-98·3), 10-year overall survival was 94·3% (95% CI 91·8-96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6-100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00-1·52]; p=0·047) and recurrence-free interval (1·45 [1·09-1·93]; p=0·011). INTERPRETATION: Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population. FUNDING: Genentech.

Blood-based biomarkers for hepatocellular carcinoma screening: Approaching the end of the ultrasound era?

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, in part because of inadequate early detection strategies. Current recommendations for screening consist of semi-annual abdominal ultrasound with or without serum alpha-fetoprotein in patients with cirrhosis and in demographic subgroups with chronic hepatitis B infection. However, this screening strategy has several deficiencies, including suboptimal early-stage sensitivity, false positives with subsequent harms, inter-operator variability in ultrasound performance, and poor adherence. A blood-based biomarker with sufficient performance characteristics for early-stage disease could overcome several of these barriers to improving early-stage detection. However, prior to use of a biomarker for screening in clinical practice, a multistep validation is required in order to understand test performance characteristics. These steps include case-control validation, followed by validation in prospective cohorts of at-risk patients. Until recently, we lacked adequate longitudinal validation cohorts for early HCC detection; however, several validation cohorts are maturing, including the Hepatocellular Carcinoma Early Detection Study and the Texas Hepatocellular Carcinoma Consortium, which will allow for rigorous validation of candidate biomarkers. While there are several promising biomarkers awaiting validation, in order to supplant abdominal ultrasound, a candidate biomarker must show adequate test performance and overcome practical hurdles to ensure adoption in clinical practice. The promise of blood-based biomarkers is significant, especially given the limitations of ultrasound-based screening; however, they require adequate validation and several logistical obstacles must be overcome prior to clinical implementation.

Detecting Early Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Using Longitudinal α-Fetoprotein Screening.

BACKGROUND & AIMS: This study aimed to evaluate the parametric empirical Bayes (PEB) longitudinal α-fetoprotein (AFP) screening algorithm performance in patients with hepatitis B compared with AFP surveillance with a fixed threshold. METHODS: The serum AFP of 588 patients was measured. Patients were screened at least once every 6 months with AFP and ultrasound or computed tomography/magnetic resonance imaging. Age, aspartate aminotransferase level, alanine aminotransferase level, platelet count, total bilirubin, prothrombin time, and hepatitis B virus DNA level were adjusted in the PEB algorithm. All variables were abstracted at the time of hepatocellular carcinoma (HCC) diagnosis for cases or last follow-up for controls and at months -6, -12, -18, -24, -30, -36, -42, -48, and -54, up to month -60. RESULTS: Overall, 62 (10.5%) HCC cases developed during a median follow-up of 52.7 months. Moreover, 55 (88.7%) cases were detected at Barcelona Clinic Liver Cancer stage 0 or A. The area under the receiver-operating characteristic curve of the patient-level true positive rate against the screening-level false positive rate was significantly higher in the PEB algorithm than that in AFP alone (area under the receiver-operating characteristic curve: 0.94 vs 0.86; P < .0005). At 80% specificity, the PEB algorithm significantly improved the patient-level true positive rate within 2 years prior to HCC diagnosis compared with AFP alone (80.6% vs 67.7%, respectively; P = .0485; adjusted P = .1663). The PEB algorithm more effectively enabled first positive screening. CONCLUSIONS: The longitudinal assessment of AFP by the PEB algorithm improved HCC screening performance compared to AFP alone in patients with hepatitis B. This algorithm may improve HCC screening without additional cost or inconvenience to patients.

The Performance of AFP, AFP-3, DCP as Biomarkers for Detection of Hepatocellular Carcinoma (HCC): A Phase 3 Biomarker Study in the United States.

BACKGROUND & AIMS: α-fetoprotein (AFP), AFP Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP) in combination or in GALAD (Gender, Age, AFP-L3, AFP, and DCP) were tested for hepatocellular carcinoma (HCC) surveillance in retrospective cohort and case-control studies. However, there is a paucity of prospective data and no phase III biomarker studies from North American populations. METHODS: We conducted a prospective specimen collection, retrospective blinded evaluation (PRoBE) cohort study in patients with cirrhosis enrolled in a 6-monthly surveillance with liver imaging and AFP. Blood samples were prospectively collected every 6 months and analyzed in a retrospective blinded fashion. True positive rate (TPR) and false positive rate (FPR) for any or early HCC were calculated within 6, 12, and 24 months of HCC diagnosis based on published thresholds for biomarkers individually, in combination and in GALAD and Hepatocellular Carcinoma Early Detection Screening (HES) scores. We calculated the area under the receiver operating curve and estimated TPR based on an optimal threshold at a fixed FPR of 10%. RESULTS: The analysis was conducted in a cohort of 534 patients; 50 developed HCC (68% early) and 484 controls with negative imaging. GALAD had the highest TPR (63.6%, 73.8%, and 71.4% for all HCC, and 53.8%, 63.3%, and 61.8 % for early HCC within 6, 12, and 24 months, respectively) but an FPR of 21.5% to 22.9%. However, there were no differences in the area under the receiver operating curve among GALAD, HES, AFP-L3, or DCP. At a fixed 10% FPR, TPR for GALAD dropped (42.4%, 45.2%, and 46.9%) and was not different from HES (36.4%, 40.5%, and 40.8%) or AFP-L3 alone (39.4%, 45.2%, and 44.9%). CONCLUSIONS: In a prospective cohort phase III biomarker study, GALAD was associated with a considerable improvement in sensitivity for HCC detection but an increase in false-positive results. GALAD performance was modest and not different from AFP-L3 alone or HES.

GALAD demonstrates high sensitivity for HCC surveillance in a cohort of patients with cirrhosis.

BACKGROUND AND AIMS: Most patients with HCC are diagnosed at a late stage, highlighting the need for more accurate surveillance tests. Although biomarkers for HCC early detection have promising data in Phase 2 case-control studies, evaluation in cohort studies is critical prior to adoption in practice. We leveraged a prospective cohort of patients with Child-Pugh A or B cirrhosis who were followed until incident HCC, liver transplantation, death, or loss to follow-up. We used a prospective specimen collection, retrospective, blinded evaluation design for biomarker evaluation of GALAD (gender × age × log alpha-fetoprotein [AFP] × des-gamma-carboxy prothrombin), longitudinal GALAD, and the HCC Early Detection Screening (HES) algorithm-compared to AFP-using patient-level sensitivity and screening-level specificity. APPROACH AND RESULTS: Of 397 patients with cirrhosis, 42 developed HCC (57.1% early stage) over a median of 2.0 years. Longitudinal GALAD had the highest c-statistic for HCC detection (0.85; 95% CI, 0.77-0.92) compared to single-time point GALAD (0.79; 95% CI, 0.71-0.87), AFP (0.77; 95% CI, 0.69-0.85), and HES (0.76; 95% CI, 0.67-0.83). When specificity was fixed at 90%, the sensitivity for HCC of single-time point and longitudinal GALAD was 54.8% and 66.7%, respectively, compared to 40.5% for AFP. Sensitivity for HCC detection was higher when restricted to patients with biomarker assessment within 6 months prior to HCC diagnosis, with the highest sensitivities observed for single-time point GALAD (72.0%) and longitudinal GALAD (64.0%), respectively. Sensitivity of single-time point and longitudinal GALAD for early-stage HCC was 53.8% and 69.2%, respectively. CONCLUSION: GALAD demonstrated high sensitivity for HCC detection in a cohort of patients with cirrhosis. Validation of these results is warranted in large Phase 3 data sets.

Body weight changes and associated predictors in a prospective cohort of young breast cancer survivors.

BACKGROUND: Weight gain after a breast cancer diagnosis is common and is associated with inferior outcomes. Young survivors may be especially susceptible to weight changes given the impact of treatment on menopausal status. METHODS: The authors identified women who were diagnosed with stage 0 to III breast cancer at age 40 years or younger between 2006 and 2016 from a multicenter prospective cohort. Self-reported weight was collected at diagnosis and at 1 year and 3 years postdiagnosis. Tumor and treatment data were obtained from medical records and patient surveys. Multinomial logistic regression was used to identify the factors associated with weight gain (≥5%) or weight loss (≥5%) versus stable weight at 1 year and 3 years postdiagnosis. RESULTS: The cohort included 956 women with a median age of 37 years at diagnosis. Mean weight significantly increased over time from 66.54 ± 14.85 kg at baseline to 67.33 ± 15.53 and 67.77 ± 14.65 kg at 1 year and 3 years, respectively (p ≤ .001 for both comparisons). The proportion of women experiencing ≥5% weight gain increased from 24.8% at 1 year to 33.9% at 3 years. At 1 year, less self-perceived financial comfort, Black race, and stage III disease were significantly associated with weight gain; at 3 years, only less self-perceived financial comfort remained significant. Baseline overweight or obesity was significantly associated with weight loss at both time points. Chemotherapy, endocrine therapy, and treatment-related menopause were not associated with weight change. CONCLUSIONS: One third of young breast cancer survivors experienced clinically significant weight gain 3 years after diagnosis; however, treatment-related associations were not observed. Age-appropriate lifestyle interventions, including the reduction of financial barriers, are needed to prevent weight gain in this high-risk population.

Doylestown Plus and GALAD Demonstrate High Sensitivity for HCC Detection in Patients With Cirrhosis.

Hepatocellular carcinoma (HCC) surveillance is associated with early tumor detection and improved survival in patients with cirrhosis.1 Surveillance is performed using semiannual abdominal ultrasound with or without α-fetoprotein (AFP); however, this strategy misses more than one-third of HCC at an early stage.2 These data highlight a need for novel surveillance strategies with higher accuracy for early HCC detection. GALAD and Doylestown Plus are novel biomarker panels that combine multiple biomarkers with patient demographic and clinical characteristics; both demonstrated promising accuracy in phase II case-control studies;3,4 however, case-control studies can overestimate biomarker performance, highlighting a need for phase III cohort and nested case-control studies.5 Our study aimed to compare multiple biomarkers (including AFP, GALAD, and Doylestown Plus) in a nested case-control study of patients with cirrhosis.