UNASSIGNED: This study aimed to explore the prognostic role of pan-immune-inflammation value (PIV) and develop a new risk model to guide individualized adjuvant systemic treatment following radiofrequency ablation (RFA) for early-stage hepatocellular carcinoma (HCC).
UNASSIGNED: Patients with early-stage HCC treated by RFA were randomly divided into training cohort A (n = 65) and testing cohort B (n = 68). Another 265 counterparts were enrolled into external validating cohort C. Various immune-inflammatory biomarkers (IIBs) were screened in cohort A. Prognostic role of PIV was evaluated and validated in cohort B and C, respectively. A nomogram risk model was built in cohort C and validated in pooled cohort D. Clinical benefits of adjuvant anti-angiogenesis therapy plus immune checkpoint inhibitor (AA-ICI) following RFA was assessed in low- and high-risk groups.
UNASSIGNED: The cutoff point of PIV was 120. High PIV was an independent predictor of unfavorable recurrence-free survival (RFS) and overall survival (OS). RFS and OS rates of patients with high PIV were significantly lower than those with low PIV both in cohort B (PRFS=0.016, POS=0.011) and C (PRFS<0.001, POS<0.001). The nomogram model based on PIV, tumor number and BCLC staging performed well in risk stratification in external validating cohort C. Adjuvant AA-ICI treatment showed an added benefit in OS (p = 0.011) for high-risk patients.
UNASSIGNED: PIV is a feasible independent prognostic factor for RFS and OS in early-stage HCC patients who received curative RFA. The proposed PIV-based nomogram risk model could help clinicians identify high-risk patients and tailor adjuvant systemic treatment and disease follow-up scheme.
Key findingsHigh pan-immune-inflammation value (PIV) is an independent indicator of unfavorable recurrence-free survival (RFS) and overall survival (OS) for early-stage hepatocellular carcinoma (HCC) patients who received curative radiofrequency ablation (RFA).Adjuvant anti-angiogenesis target therapy plus immune checkpoint inhibitor (AA-ICI) treatment showed added benefit in OS for the high-risk patients defined by a nomogram risk model based on PIV, tumor number and BCLC staging.What is known and what is new?Inflammation and impaired host immunity are associated with carcinogenesis and progression of HCC. Increasing evidences showed that immune-inflammatory biomarkers (IIBs) had prognostic roles in early-stage HCC patients who received RFA. However, prognostic potential of PIV has not been determined in this setting.Herein, high PIV was first reported to be an independent risk factor of poor RFS and OS in early-stage HCC patients treated by curative RFA and helped to discriminate patients between low- and high-risk groups. Adjuvant AA-ICI treatment following RFA was beneficial to OS of patients in the high-risk group.What is the implication, and what should change now?For early-stage HCC with high-risk factors (high PIV, multiple tumor foci and more advanced BCLC stage), intensive follow-up and adjuvant systemic therapy following curative RFA were warranted.

BACKGROUND: In melanoma treatment, an approach following positive sentinel lymph node biopsy (SLNB) has been recently deescalated from completion lymph node dissection (CLND) to active surveillance based on phase III trials data. In this study, we aim to evaluate treatment strategies in SLNB-positive melanoma patients in real-world practice.
METHODS: Five-hundred-fifty-seven melanoma SLNB-positive patients from seven comprehensive cancer centers treated between 2017 and 2021 were included. Kaplan-Meier methods and the Cox Proportional-Hazards Model were used for analysis.
RESULTS: The median follow-up was 25 months. Between 2017 and 2021, the percentage of patients undergoing CLND decreased (88-41%), while the use of adjuvant treatment increased (11-51%). The 3-year OS and RFS rates were 77.9% and 59.6%, respectively. Adjuvant therapy prolonged RFS (HR:0.69, p = 0.036)), but CLND did not (HR:1.22, p = 0.272). There were no statistically significant differences in OS for either adjuvant systemic treatment or CLND. Lower progression risk was also found, and time-dependent hazard ratios estimation in patients treated with systemic adjuvant therapy was confirmed (HR:0.20, p = 0.002 for BRAF inhibitors and HR:0.50, p = 0.015 for anti-PD-1 inhibitors).
CONCLUSIONS: Treatment of SLNB-positive melanoma patients is constantly evolving, and the role of surgery is currently rather limited. Whether CLND has been performed or not, in a group of SLNB-positive patients, adjuvant systemic treatment should be offered to all eligible patients.

OBJECTIVE: The large variation in histologic grading of invasive breast cancer (IBC) that has been reported likely influences tailoring adjuvant therapy. The role of grading in therapeutic decision-making in daily practice, was evaluated using the Dutch national guidelines for IBC-management.
METHODS: Synoptic reports of IBC resection-specimens, obtained between 2013 and 2016, were extracted from the nationwide Dutch Pathology Registry, and linked to treatment-data from the Netherlands Cancer Registry. The relevance of grading for adjuvant chemotherapy (aCT) was quantified by identifying patients for whom grade was the determinative factor. In addition, the relation between grade and aCT-administration was evaluated by multivariate logistic regression for patients with a guideline-aCT-indication.
RESULTS: 30,843 patients were included. Applying the guideline that was valid between 2013 and 2016, grade was the determinative factor for the aCT-indication in 7744 (25.1%) patients, a percentage that even increased according to the current guideline where grade would be decisive for aCT in 10,869 (35.2%) patients. Also in current practice, the indication for adjuvant endocrine therapy (aET) would be based on grade in 9173 (29.7%) patients. Finally, as patients with lower-grade tumors receive aCT significantly less often, grade was also decisive in tailoring aCT de-escalation.
CONCLUSIONS: In the largest study published so far we illustrate the increasing importance of histologic grade in tailoring adjuvant systemic breast cancer therapy. Next to playing a key-role in aCT-indication and de-escalation, the role of grading has expanded to the indication for aET. Optimizing histologic grading by pathologists is urgently needed to diminish the risk of worse patient outcome due to non-optimal treatment.

BACKGROUND: The Oncotype DX is a quantitative assay of the expression of 16 tumor-related genes and 5 reference genes that predicts the potential of adjuvant chemotherapy benefit in estrogen receptor (ER)-positive early breast cancer patients. The study aims to evaluate the impact of Oncotype DX as a tool for adjuvant treatment decision of ER-positive, HER2-negative, N0/N1 early-stage breast cancer patients and to determine which clinicopathological criteria derived the greatest advantage.
RESULTS: A hundred patients at a median age of 50 years were included. TNM stage distribution was 34, 63, and 3 patients for stages I, II, and IIIA respectively. Fifty-four patients had luminal A and 46 had luminal B tumors. The recurrence score (RS) results were low, intermediate, and high risk in 54, 34, and 12 patients respectively. Before the test results, adjuvant chemoendocrine therapy (CET) was recommended for 46 patients while 54 were advised for endocrine therapy (ET). After getting the test results, 25 patients received CET (1, 12, and12 patients in the low-, intermediate-, and high-risk groups respectively) and 75 received ET. Treatment change was documented in 37 patients (8 patients from ET to CET and 29 from CET to ET; p = 0.001, McNemar test). Treatment change was significant among patients ≤ 50 years, luminal B tumors, stage II and IIIA disease, and node-positive disease.
CONCLUSIONS: Oncotype DX testing resulted in significant changes in the adjuvant treatment decisions in ER-positive, HER2-negative early breast cancer particularly in the case of young, luminal B, N1, and stage II-IIIA disease.

BACKGROUND: The association of HER2 status with urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) levels raises the question whether uPA/PAI-1 level carries additional clinically relevant prognostic information independently from HER2 status. The aim of our study was to compare the prognostic value of uPA/PAI-1 level, HER2 status, and traditional prognostic factors for survival in node-negative breast cancer patients.
METHODS: A retrospective analysis of 858 node-negative breast cancer patients treated in Maribor University Clinical Center, Slovenia, in the years 2000-2009 was performed. Data were obtained from patient medical records. The median follow-up time was 100 months. Univariate and multivariate analyses of disease-free (DFS) and overall survival (OS) were performed using the Cox regression and the Cox proportional hazards model.
RESULTS: In univariate analysis, age, tumor size, grade, lymphovascular invasion, HER2 status and UPA/PAI-1 level were associated with DFS, and age, tumor size, grade, and uPA/PAI-1 level were associated with OS. In the multivariate model, the most important determinants of DFS were age, estrogen receptor status and uPA/PAI-1 level, and the most important factors for OS were patient age and tumor grade. The HR for death from any cause in the multivariate model was 1.98 (95% CI 0.83-4.76) for patients with high uPA and/or PAI-1 compared to patients with both values low.
CONCLUSIONS: uPA/PAI-1 level clearly carries an independent prognostic value regardless of HER2 status in node-negative breast cancer and could be used in addition to HER2 and other markers to guide clinical decisions in this setting.

The Breast Cancer Disease Site Group of Cancer Care Ontario identified the need for new guidelines for the adjuvant systemic therapy of early-stage breast cancer. The specific question to be addressed was \"What is the optimal adjuvant systemic therapy for female patients with early-stage operable breast cancer, when patient and disease factors are considered?\" A systematic review was prepared based on literature searches conducted using the medline and embase databases for the period January 2008 to March 5, 2012, and updated to May 12, 2014. Guidelines were located from that search, from the Standards and Guidelines Evidence directory of cancer guidelines, and from the Web sites of major guideline organizations. The literature located was subdivided into the broad categories of chemotherapy, hormonal therapy, and therapy targeted to her2 (human epidermal growth factor receptor 2). Although several of the systemic therapies discussed in this guideline can be considered in the neoadjuvant setting, the review focused on trials with rates of disease-free and overall survival as endpoints and thus excluded several trials that used pathologic complete response as a primary endpoint. Based on the systematic review, the working group drafted recommendations on the use of chemotherapy, hormonal therapy, and targeted therapy; based on their professional experience, they also drafted recommendations on patient and disease characteristics and recurrence risk. The literature review and draft recommendations were circulated to a consensus panel of medical oncologists who had expertise in breast cancer and who represented the regions of Ontario. Items without initial consensus were discussed at an in-person consensus meeting held in Toronto, November 23, 2012. The final recommendations are those for which consensus was reached before or at the meeting. Some of the key evidence was revised after the updated literature search. Evidence reviews for systemic chemotherapy, endocrine therapy, and targeted therapy for her2-positive disease are reported in separate articles in this supplement. The full three-part 1-21 evidence-based series, including complete details of the development and consensus processes, can be found on the Cancer Care Ontario Web site at https://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/breast-ebs.

BACKGROUND: Oncotype DX recurrence score is a multi-gene assay which quantifies the risk of distant recurrence in patients with hormone receptor-positive (HR+) early breast cancer (EBC) treated with tamoxifen, and predicts the magnitude of clinical benefit of adjuvant chemotherapy. This retrospective study examined factors that were associated with use of Oncotype DX assay at a tertiary care cancer centre in Ottawa, Canada.
METHODS: One hundred consecutive patients (pts) diagnosed with HR+, HER2/neu negative EBC (stage I-II), who underwent Oncotype DX testing (Test Group) between 1st April 2010, and 30th June 2011 were included in the study. A second cohort of 100 randomly selected patients with HR+, HER2/neu negative EBC diagnosed from the same time period who did not receive Oncotype DX testing were used as the control group (Control Group). Demographic and clinicopathologic data were obtained from review of charts. Logistic regression was performed to identify variables associated with Oncotype DX usage.
RESULTS: Median age was 58 years (r: 26-77) in Test Group and 63 years (r: 30-81) in Control Group. Sixty-two patients in the Test Group had T1 tumours, compared with 71 in the Control Group. The median 10-year recurrence risks from Adjuvant! Online were 19% and 12% in the Test Group and Control Group, respectively. Factors significantly associated with the utilisation of Oncotype DX assay on multivariate analysis include age 50-64 (p=0.049), tumour size 10.1-20mm (p=0.008) and grade 2 histological grade (p=0.004).
CONCLUSIONS: Usage of Oncotype DX assay is associated with several clinicopathological factors. These factors reflect the clinical uncertainty of benefit from chemotherapy in these subpopulations of patients and suggest how Oncotype DX assay could complement clinicopathological factors in helping clinicians on treatment selection.

BACKGROUND: The cost-effectiveness of the 70-gene signature (70-GS) (MammaPrint®) has earlier been estimated using retrospective validation data. Based on the prospective 5-year survival data of the microarRAy-prognoSTics-in-breast-cancER (RASTER) study, the aim here was to evaluate the cost-effectiveness reflecting the actual use in clinical practice, including reality-based compliance rates.
METHODS: Costs and outcomes (quality-adjusted-life-years (QALYs)) were calculated in node-negative (N-) patients included in the RASTER study (n=427). Sensitivity and specificity of the 70-gene and Adjuvant! Online (AO) were based on 5-year distant-disease-free survival (DDFS). Subgroup analyses were performed for two groups for whom benefit of the 70-gene had earlier been reported: (1) ductal, oestrogen receptor-positive (ER+), tumour diameter 10-30 mm, grade II, age 40-70; (2) ductal, oestrogen receptor-positive, tumour diameter 5-30 mm, grade II/III and age 40-70.
RESULTS: Based on 5-year survival data, the cost-effectiveness of the 70-gene signature versus AO was prospectively confirmed. The total health care costs per patient were €26,786 for the 70-gene and €29,187 for AO. The quality adjusted life years yielded 12.49 and 11.88, respectively. The subgroups retrieved slightly higher life gains and higher costs, but all resulted finally in a favourable position for the 70-gene signature.
CONCLUSIONS: The use of the 70-gene signature, as judged appropriate by doctors and patients and supported by a low risk 70-gene signature as an oncological safe choice, was also found to be cost-effective.