Increased life expectancy as a result of non-hormonal targeted therapies for HER2 or hormone receptor positive metastatic breast cancer: a systematic review and meta-analysis

This article aimed to assess the clinical effectiveness of non-hormonal targeted therapies (TTs) in terms of increase of median progression-free survival (PFS) and overall survival (OS) in receptor-positive metastatic breast cancer (MBC) patients by performing a systematic review and meta-analysis. We systematically searched relevant randomized controlled trials and extracted data about number of patients on targeted and comparator therapy, receptor status, line of treatment, median PFS and OS, p values, hazard ratios (HRs) and 95% confidence intervals (CI). Inverse variance was used to estimate pooled HRs, chi-square test for heterogeneity and Jadad scale for quality were applied. Thirty-eight studies (n = 17,192 patients) were eligible for inclusion. TTs added 3.3 months to the median PFS [0.7-9.6; HRs 0.74, 95% CI 0.71-0.77] of receptor-positive MBC patients and prolonged their median OS with 3.5 months [0-4.7; HRs 0.90, 95% CI 0.82-0.98]. The highest increase in median PFS of 3.6 months was found in HER2-/hormone receptor(HR)+ patients, while the highest increase in median OS of 7.2 months was observed in HER2+/HRmixed status patients. First-line ITs were most effective in increasing the median PFS in the HR+/HER2- group with 2.0 months, and in the HER2+/HRmixed group by adding 4.7 months to the median OS. Second-line TTs were most effective for HER2-/HR+ patients by adding 2.6 months to their PFS, and for HER2+/HRmixed patients by adding 3.1 months to their median OS. Albeit small, the gain in months of median PFS and median OS was significant. Importantly, the results reported show large variation, and thus routinely applying a personalized approach seems warranted. (C) 2017 Elsevier Ltd. All rights reserved

Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma patients in the Netherlands: a retrospective cohort study

Background: Vismodegib has been used for the treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC) since 2011. Most efficacy and safety data are provided by clinical trials. This study evaluates the effectiveness of vismodegib for the treatment of laBCC, mBCC and basal cell nevus syndrome (BCNS) patients, and the tumour characteristics associated with a higher probability of achieving a complete response in the Netherlands. Methods: A retrospective cohort study that included all patients ≥18 years with histologically proven basal cell carcinoma that received ≥1 dose of vismodegib between July 2011 and September 2019 in the Netherlands. Results: In total, 48 laBCC, 11 mBCC and 19 BCNS patients were included. Median progression-free survival was 10.3 months (95% confidence interval (CI), 7.5–22.6) for laBCC, 11.7 (95% CI, 5.2–17.5) for mBCC and 19.1 (95% CI, 7.4–20.2) for BCNS. Larger laBCCs were associated with a lower probability of complete response (hazard ratio (HR) 0.77 per increase in cm, p = 0.02). Of all BCNS patients, 63% received ≥2 treatment sequences with vismodegib; all achieved partial responses. Conclusions: Half of the aBCC patients progress within 1 year after the start of vismodegib treatment. More research is needed to investigate other treatment strategies after vismodegib progression and to evaluate long-term effects of repetitive vismodegib treatment

Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer

<div><p>Copper metabolism MURR1 domain 1 (COMMD1) protein is a multifunctional protein, and its expression has been correlated with patients’ survival in different types of cancer. <i>In vitro</i> studies revealed that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC) patients. We found that elevation of nuclear COMMD1 expression sensitized A2780 ovarian cancer cells to cisplatin-mediated cytotoxicity. This was accompanied by a more effective G₂/M checkpoint, and decreased protein expression of the DNA repair gene <i>BRCA1</i>, and the apoptosis inhibitor <i>BCL2</i>. Furthermore, COMMD1 expression was immunohistochemically analyzed in two tissue micro-arrays (TMAs), representing a historical cohort and a randomized clinical trial-based cohort of advanced stage HGSOC tumor specimens. Expression of COMMD1 was observed in all ovarian cancer samples, however, specifically nuclear expression of COMMD1 was only observed in a subset of ovarian cancers. In our historical cohort, nuclear COMMD1 expression was associated with an improved response to chemotherapy (OR = 0.167; <i>P</i> = 0.038), although this association could not be confirmed in the second cohort, likely due to sample size. Taken together, these results suggest that nuclear expression of COMMD1 sensitize ovarian cancer to cisplatin, possibly by modulating the G₂/M checkpoint and through controlling expression of genes involved in DNA repair and apoptosis.</p></div

Antibody validation and exploratory immunostaining for COMMD1 in human ovarian tumor samples.

<p><b>(A)</b> Representative immunohistochemical COMMD1 staining in paraffin embedded HEK293T and HeLa cells depleted for COMMD1. <b>(B)</b> HEK293T and HeLa cells were stably silenced for COMMD1 as shown by immunoblotting. (<b>C</b>) Observational immunostainings for COMMD1, including its control IgG₁ immunostaining in a consecutive slide, in HGSOC patient samples demonstrating either absent or presence of nuclear COMMD1. (<b>D</b>) Quantification workflow of immunohistochemical COMMD1 staining. Image analysis was performed using the ImageJ-based software package FIJI. DAB staining and hematoxylin staining were deconvoluted and images were subsequently converted into 8-bit gray scale images. Hematoxylin staining was used to define cytoplasm/nucleus boundaries. Vectors were subsequently used to measure DAB staining intensities across cells and quantify nuclear COMMD1 levels in relation to cytoplasmic levels. (B) Three ‘nuclear COMMD1-negative’ (n = 10 cells per tumor sample) and three ‘nuclear COMMD1-positive’ tumor samples were analyzed. Averages and standard deviations are indicated. Relative nuclear COMMD1 levels to cytoplasmic levels are plotted per tumor sample.</p

Examples of COMMD1 levels and localization in ovarian cancer samples.

<p><b>(A)</b> Representative immunohistochemical stainings of cytoplasmic and nuclear COMMD1 are indicated. <b>(B)</b> Representative immunohistochemical stainings of cytoplasmic and nuclear COMMD1 of responders (n = 3) and non-responders (n = 3).</p

Response to therapy for TMA1: logistic regression analysis for advanced stage HGSOC patients with ≥2 cm residual disease after primary surgery, and receiving platinum-based chemotherapy and a PFS of <6 months (n = 14) versus PFS of >18 months (n = 16).

<p>Response to therapy for TMA1: logistic regression analysis for advanced stage HGSOC patients with ≥2 cm residual disease after primary surgery, and receiving platinum-based chemotherapy and a PFS of <6 months (n = 14) versus PFS of >18 months (n = 16).</p

Increased nuclear COMMD1 expression in A2780 cells enhanced cisplatin sensitivity.

<p><b>(A)</b> Subcellular localization of COMMD1 in A2780 EV and A2780-COMMD1 cells determined by immunoblotting. Intensity of individual bands for COMMD1 was quantified using ImageLab software. After correction for tubulin or lamin A/C expression the relative COMMD1 expression in A2780-COMMD1 cells was determined. <b>(B)</b> A2780 EV and A2780 COMMD1 cells were stained for COMMD1 (green), and DNA (blue) and imaged by fluorescent microscopy. The scale bar represents 20 μm. <b>(C)</b> A2780 EV and A2780 COMMD1 cells were plated in 96-well plates and treated with indicated concentrations of cisplatin. After 72 hours of treatment, cells were incubated with MTT for 3 hours and the viability of cells was determined by colorimetric measurement. Data are shown from three independent experiments. Statistical significance was calculated using the Student's t-test. *: <i>P</i>< 0.05, **: <i>P</i> <0.01, ***: <i>P</i> <0.001. <b>(D)</b> Overexpression of COMMD1 in Peo14 cells augments cisplatin sensitivity. Control cells (Peo14 EV) and Peo14 cells stably overexpressing COMMD1-Flag (Peo14 COMMD1) were plated in 96-well plates and treated with indicated concentrations of cisplatin. After 72 hours of treatment, cells were incubated with MTT for 3 hours and the viability of cells was determined by colorimetric measurement. Data are shown from three independent experiments. Statistical significance was calculated using the Student's t-test. *: <i>P</i>< 0.05. (<b>E</b>) Subcellular localization of COMMD1 in Peo14-EV and Peo14-COMMD1 cells determined by immunoblotting. Intensity of individual bands for COMMD1 was quantified using ImageLab software. <b>(F)</b> Silencing of COMMD1 results in decreased sensitivity of A2780 cells to cisplatin. Control cells (EV) and COMMD1 silenced A2780 cells (KD) were plated in 96-well plates and treated with indicated concentrations of cisplatin. After 72 hours of treatment, cells were incubated with MTT for 3 hours and the viability of cells was determined by colorimetric measurement. Data are shown from three independent experiments. Statistical significance was calculated using the Student's t-test. *: <i>P</i>< 0.05</p

Model of how COMMD1 may influence responses to cisplatin.

<p>Model of how COMMD1 may influence responses to cisplatin.</p