Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer.

PURPOSE: Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody-drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623). PATIENTS AND METHODS: Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity. RESULTS: Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% [95% confidence interval (CI): 13%-37%]. Median duration of response (DOR) was 4.2 months (range: 1.0+-9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%-43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%-35%), median DOR of 6.0 months (range: 1.0+-9.7), and 6-month PFS rate of 40% (95% CI: 24%-55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed. CONCLUSIONS: Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.

Recurrence dynamics of breast cancer according to baseline body mass index.

BACKGROUND: In cancer follow-up, in addition to the evaluation of survival probabilities, there is a fundamental need of assessing recurrence dynamics for optimal disease management. Although the time-dependent effect of the oestrogen receptor (ER) status of the tumour has already been described, so far no factor has proven to disentangle the multi-peak behaviour observed for breast cancer recurrences. Here, we aimed at investigating whether adiposity at diagnosis, reflected by increased patient's body mass index (BMI), could be associated with breast cancer recurrence patterns over time after primary cancer therapy. METHODS: We retrieved BMI from 734 of 777 patients with node-positive breast cancer from a phase III randomised clinical trial, which compared different chemotherapy regimens and had a median follow-up of 15.4 years. Cumulative incidence estimation as well as piecewise exponential models were carried out to estimate the distant recurrence dynamics, in all patients, as well as in subgroups based on the ER status, with the ER-positive group being further split according to the menopausal status. RESULTS: In patients with ER-negative breast cancer, time-dependent analyses revealed that the hazard of late relapses could mainly be attributed to the overweight and obese patients. Within the subgroup of premenopausal patients with ER-positive tumours, obesity was associated with an early high narrow peak of distant recurrences followed by another main peak after 5 years of follow-up. The risk for overweight patients was intermediate between obese and normal-weight patients. In the postmenopausal subgroup of patients with ER-positive tumours, the distant recurrence rate was significantly more elevated in the overweight patients compared to the other BMI categories, and a second late peak of recurrences was also observed for the obese patients. CONCLUSION: These results demonstrate that the patient's BMI at diagnosis is associated with cancer recurrence dynamics. Patient adiposity should therefore be central to the exploration of late adjuvant treatment modalities.

Cardiac assessment of early breast cancer patients 18 years after treatment with cyclophosphamide-, methotrexate-, fluorouracil- or epirubicin-based chemotherapy.

BACKGROUND: Epirubicin-based chemotherapy improves the outcome of early breast cancer (BC) patients. However, cardiotoxicity remains an important side effect. METHODS: We re-consented node-positive BC patients enrolled in a phase III trial between 1988 and 1996 which compared six cycles of oral cyclophosphamide, methotrexate, fluorouracil (CMF) versus two epirubicin-cyclophosphamide regimens differing by the anthracycline cumulative dose [standard-dose epirubicin and cyclophosphamide (SDE) (8 × 60 mg/m(2)) and higher-dose epirubicin and cyclophosphamide (HDE) (8 × 100 mg/m(2))]. Eligible patients were those who were alive and free of disease and had no contra-indications to the proposed tests (cardiac evaluation). Cardiotoxicity was defined as asymptomatic systolic dysfunction (left ventricular ejection fraction (LVEF)< 50%, New York Heart Association (NYHA) Class I) or symptomatic heart failure (NYHA Class II-IV). Differences in cardiotoxicity between CMF and SDE/HDE were assessed using chi-square and Fisher Exact tests for binary variables and t-test and Wilcoxon test for continuous variables. RESULTS: Among the 777 patients, 20 cases of CHF were reported (CMF = 1, SDE = 5, HDE = 14; p < 0.001). Between September 2010 and June 2013, 82 patients (30%) out of 269 eligible patients accepted to participate in this substudy. Median follow-up was 18 years (range 15-24). Epirubicin-treated patients had significantly higher heart rate, more abnormal echocardiograms and LVEF by magnetic resonance imaging (MRI) compared to CMF-treated ones. A trend towards higher BNP was also observed in the SDE/HDE group (P = 0.08). No differences were observed in LVEF assessed by echocardiogram or troponin T levels. CONCLUSIONS: Participation rate in this substudy was lower than expected highlighting the complexity of re-calling patients several years after the initial BC diagnosis. After 18 years, epirubicin-treated patients had a lower LVEF by MRI, more abnormal echocardiograms, higher heart rates compared to patients treated with CMF. However, no major delayed cardiotoxicity was observed.

Genomic Grade Index (GGI): feasibility in routine practice and impact on treatment decisions in early breast cancer.

PURPOSE: Genomic Grade Index (GGI) is a 97-gene signature that improves histologic grade (HG) classification in invasive breast carcinoma. In this prospective study we sought to evaluate the feasibility of performing GGI in routine clinical practice and its impact on treatment recommendations. METHODS: Patients with pT1pT2 or operable pT3, N0-3 invasive breast carcinoma were recruited from 8 centers in Belgium. Fresh surgical samples were sent at room temperature in the MapQuant Dx™ PathKit for centralized genomic analysis. Genomic profiles were determined using Affymetrix U133 Plus 2.0 and GGI calculated using the MapQuant Dx® protocol, which defines tumors as low or high Genomic Grade (GG-1 and GG-3 respectively). RESULTS: 180 pts were recruited and 155 were eligible. The MapQuant test was performed in 142 cases and GGI was obtained in 78% of cases (n=111). Reasons for failures were 15 samples with <30% of invasive tumor cells (11%), 15 with insufficient RNA quality (10%), and 1 failed hybridization (<1%). For tumors with an available representative sample (≥ 30% inv. tumor cells) (n=127), the success rate was 87.5%. GGI reclassified 69% of the 54 HG2 tumors as GG-1 (54%) or GG-3 (46%). Changes in treatment recommendations occurred mainly in the subset of HG2 tumors reclassified into GG-3, with increased use of chemotherapy in this subset. CONCLUSION: The use of GGI is feasible in routine clinical practice and impacts treatment decisions in early-stage breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT01916837, http://clinicaltrials.gov/ct2/show/NCT01916837.

Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study.

PURPOSE: The 4-year results of this trial demonstrated that a higher dose of epirubicin with cyclophosphamide (HEC) is superior to a lower dose of epirubicin, 60 mg/m(2) (EC), for event-free survival (EFS; 27% reduction), but is not superior to classical oral cyclophosphamide, methotrexate, and fluorouracil (CMF) in the adjuvant treatment of node-positive breast cancer. Herein we report the 15-year data on efficacy and long-term toxicity of this three-arm Belgian multicenter trial. PATIENTS AND METHODS: Between March 1988 and December 1996, 777 eligible patients were randomly assigned to six cycles of CMF, eight cycles of EC, or eight cycles HEC. RESULTS: The 15-year EFS was 45% for patients who received CMF, 39% for patients who received EC, and 50% for patients who received HEC. The hazard ratios (HR) were 0.77 for HEC versus EC (95% CI, 0.60 to 0.98; P = .03), 0.90 for HEC versus CMF (P = .39), and 0.86 for EC versus CMF (P = .21). No difference in overall survival (OS) was seen. Cardiac toxicity was more frequent with HEC than with CMF (11 patients v 1 patient; P = .006), but no more than with EC (P = .21). CONCLUSION: Treatment with HEC demonstrated superior EFS when compared with lower-dose epirubicin. However, we do not recommend the use of HEC regimen in daily clinical practice, mainly because of the higher risk of cardiotoxicity related to the cumulative doses of epirubicin and the lack of superiority of anthracyclines over CMF in our study.