Significantly longer time to deterioration of quality of life due to CANKADO PRO-React eHealth support in HR+ HER2- metastatic breast cancer patients receiving palbociclib and endocrine therapy: primary outcome analysis of the multicenter randomized AGO-B WSG PreCycle trial.

BACKGROUND: The multicenter, randomized, phase IV, intergroup AGO-B WSG PreCycle trial (NCT03220178) evaluated the impact of CANKADO-based electronic patient-reported outcome (ePRO) assessment on quality of life (QoL) in hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer (MBC) patients receiving palbociclib and an aromatase inhibitor or palbociclib + fulvestrant. CANKADO PRO-React, a European Union-registered medical device, is an interactive autonomous application reacting to patient self-reported observations. PATIENTS AND METHODS: Between 2017 and 2021, 499 patients (median age 59 years) from 71 centers were randomized (2 : 1, stratified by therapy line) between an active version of CANKADO PRO-React (CANKADO-active arm) and a version with limited functionality (CANKADO-inform arm). A total of 412 patients (271 CANKADO-active; 141 CANKADO-inform) were available for analysis of the primary endpoint, time to deterioration (TTD) of QoL [10-point drop on the Functional Assessment of Cancer Therapy-General (FACT-G) score], using an Aalen-Johansen estimator for cumulative incidence function of TTD DQoL (QoL deterioration) with 95% pointwise confidence intervals (CIs). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and DQoL. RESULTS: In all patients [intention-to-treat (ITT)-ePRO], cumulative incidence of DQoL was significantly more favorable (lower) in the CANKADO-active arm (hazard ratio 0.698, 95% CI 0.506-0.963). Among first-line patients (n = 295), the corresponding hazard ratio was 0.716 (0.484-1.060; P = 0.09), and in second-line patients (n = 117) it was 0.661 (0.374-1.168; P = 0.2). Absolute patient numbers declined in later visits; FACT-G completion rates were 80% and higher until about visit 30. Mean FACT-G scores showed a steady decline from baseline and an offset in favor of CANKADO-active. No significant differences in clinical outcome were observed between arms: median PFS (ITT population) was 21.4 (95% CI 19.4-23.7) (CANKADO-active) and 18.7 (15.1-23.5) months (CANKADO-inform); median OS was not reached (CANKADO-active) and 42.6 months (CANKADO-inform). CONCLUSIONS: PreCycle is the first multicenter randomized eHealth trial demonstrating a significant benefit for MBC patients receiving oral tumor therapy when using an interactive autonomous patient empowerment application.

Impact of trastuzumab treatment beyond disease progression for advanced/metastatic breast cancer on survival - results from a prospective, observational study in Germany.

OBJECTIVES: Evidence suggests that continued trastuzumab therapy beyond progression (TBP) may provide additional survival benefit. Within the framework of an observational prospective study of patients with advanced/metastatic breast cancer receiving trastuzumab in routine clinical practice, we had the opportunity to examine the effect of TBP in a large population. PATIENTS AND METHODS: Among a total of 1843 trastuzumab-treated patients, a sub-cohort of 418 fulfilled the selection criteria for the TBP analysis: 261 continued trastuzumab and 157 discontinued. Logrank tests and Cox models were used to compare survival and identify prognostic factors. RESULTS: Survival from progression was significantly longer in those patients continuing trastuzumab treatment beyond disease progression (TBP: median 22.1 months; no TBP: median 14.9 months; HR = 0.64; P = 0.00021). In addition to TBP, a positive endocrine receptor status, a longer relapse-free interval, no visceral metastasis, no concomitant chemotherapy during first-line treatment, and first-line response were independently significant prognostic variables for longer survival on multivariate analysis. CONCLUSION: The hitherto limited evidence for TBP benefit from randomized studies was confirmed. While a number of strong disease-related predictors for survival after first progression could be identified, the positive effect of trastuzumab continuation retained statistical significance in a multivariate model.

Mutant p53: "gain of function" through perturbation of nuclear structure and function?

Mutant p53 not simply is an inactivated tumor suppressor, as at least some mutant p53 proteins exhibit oncogenic properties. Mutant p53 thus is the most commonly expressed oncogene in human cancer. Accordingly, the expression of mutant p53 in tumors often correlates with bad prognosis, and expression of mutant p53 in p53-negative tumor cells enhances their transformed phenotype. The molecular basis for this "gain of function" is not yet understood. However, the finding that mutant p53 tightly associates with the nuclear matrix in vivo, and with high affinity binds to nuclear matrix attachment region (MAR) DNA in vitro, suggests that these activities are connected and may result in perturbation of nuclear structure and function in tumor cells. MAR-binding of mutant p53 most likely is due to conformation-selective DNA binding by mutant p53, i.e. the specific interaction of a given mutant p53 protein with regulatory or structural genomic DNA elements that are able to adopt specific non-B-DNA conformations. In support to this assumption, human mutant p53 (Gly(245)-->Ser) was shown to bind to repetitive DNA elements in vivo that might be part of MAR elements. This further supports a model according to which mutant p53, by interacting with key structural components of the nucleus, exerts its oncogenic activities through perturbation of nuclear structure and function. J. Cell. Biochem. Suppl. 35:115-122, 2000.