Randomized phase 3 efficacy and safety trial of proposed pegfilgrastim biosimilar MYL-1401H in the prophylactic treatment of chemotherapy-induced neutropenia.

Pegfilgrastim is indicated for reducing the duration of neutropenia and incidence of febrile neutropenia in patients receiving cytotoxic chemotherapy. Here, safety and efficacy of MYL-1401H, a proposed pegfilgrastim biosimilar, were investigated as prophylaxis for chemotherapy-induced neutropenia. This was a phase 3, multicenter, randomized, double-blind, parallel-group equivalence trial of MYL-1401H vs European Union-sourced reference pegfilgrastim. Patients with newly diagnosed stage II/III breast cancer eligible to receive (neo) adjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide every 3 weeks for 6 cycles were enrolled and randomized 2:1 to 6 mg of MYL-1401H or reference pegfilgrastim 24 h (+ 2-h window after the first 24 h) after the end of chemotherapy. The primary efficacy endpoint was the duration of severe neutropenia in cycle 1 (i.e., days with absolute neutrophil count (ANC) < 0.5 × 109/L). Mean (standard deviation (SD)) duration of severe neutropenia in MYL-1401H and reference pegfilgrastim groups was 1.2 days (0.93) and 1.2 days (1.10), respectively. The 95% CI for least squares mean difference (- 0.285, 0.298) was within the predefined equivalence range of ± 1 day. Secondary endpoints, including grade ≥ 3 neutropenia (frequency, 91% and 82% for MYL-1401H and reference pegfilgrastim, respectively), time to ANC nadir (mean (SD), 6.2 (0.98) and 6.3 (1.57) days), and duration of post-nadir recovery (mean (SD), 1.9 (0.85) and 1.7 (0.91) days) were comparable. Overall safety profiles of the study drugs were comparable. MYL-1401H demonstrated equivalent efficacy and similar safety to reference pegfilgrastim and may be an equivalent option for reducing incidence of neutropenia. ( ClinicalTrials.gov , NCT02467868; EudraCT, 2014-002324-27).

HER2 blockade in metastatic collecting duct carcinoma (CDC) of the kidney: a case report.

BACKGROUND: Collecting duct carcinoma of the kidney (CDC) is a rare cancer associated with bad prognosis and, at present, with no specific effective therapies. CASE REPORT: We report a clinical case with disseminated highgrade CDC presenting with widespread metastasis to both lungs, pelvic bones, axial skeleton, and the central nervous system (posterior fossa, both hemispheres and pituitary-hypothalamic). The primary tumor in the kidney was demonstrated (by fluorescence in situ hybridization and immunohistochemistry with Herceptest (3+ score)) to significantly overexpress HER2. Critically ill at presentation, the patient received oral capecitabine together with double HER2 blockade with both intravenous trastuzumab and oral lapatinib. His clinical response was a dramatic improvement and a progressive decline in the radiological size of all of his multiple cancer lesions. CONCLUSION: Double HER2 blockade is an effective therapy in disseminated CDC even in the presence of brain metastases.

Are aggressive epithelial cancers 'a disease' of Eutherian mammals?

Placental immune editing switches (PIES) have not evolved to prevent or to cause cancer but to make feto-maternal immune tolerance possible, which is at the very core of our placental mammalian ('Eutherian') nature. Aggressive epithelial cancers might be an unfortunate 'side effect' of this highly sophisticated biological nature. Microenvironmental properties in the placenta and decidua are thought to be a key to feto-maternal immune tolerance. Recently, in 2016-2018, we published the first human genomic and epigenomic evidence of similar gene expression profiles in immune regulatory genes in cancer (primary lobular infiltrating breast cancer and ipsilateral axillary metastatic lymph nodes) and both placenta and decidua of the same young patient with breast carcinoma during pregnancy. These findings led us to speculate that ectopic expression, or repression, of 'PIES' might be used by cancer cells during carcinogenesis or cancer progression to elude immune vigilance in spite of tumour-associated antigens or evolving neo antigenic landscapes. Cancers are well known to frequently express embryonic antigens, such as carcinoembryonic antigen, used as cancer markers and detectable in the blood circulation, or to express ectopic hormones. Why should cancer cells invent de novo complex new immune suppression mechanisms, if they could simply use innate ones developed during the long-term evolution of placental mammals in order to hide fetal paternal antigens from the mother's own immune system? Monotremata (Prototheria-like Echidnas or Platypus Ornithoryncus) are nonplacental egg-laying mammals and, in spite of rudimentary breast epithelial ducts and lobules, they are seldom reported to suffer from aggressive breast cancers.

Epigenetic changes found in uterine decidual and placental tissues can also be found in the breast cancer microenvironment of the same unique patient: description and potential interpretations.

Microenvironmental properties are thought to be responsible for feto-maternal tolerance. Speculatively, ectopic expression of placental gene programs might also be related to cancer cells' ability to escape from immune vigilance mechanisms during carcinogenesis and cancer progression. Recently, we published the first human genomic evidence of similar immune related gene expression profiles in both placenta (placenta and decidual tissue) and cancer (both primary and metastatic) in the same patient with lymph-node positive breast carcinoma during pregnancy. Here we report the first epigenomic analysis of these tissue samples and describe their main findings, with respect to immune related genes regulation (over or under expressed) in cancer cells with regards placental tissues. We confirm significant similarities, and hierarchical clustering (both unsupervised and supervised), in CpG island methylation patterns between decidual/placental and cancer microenvironments, which cannot be easily explained by simple models or unique pathways. Several different cell types are probably involved in these complex immune regulation mechanisms. Cancers may somehow "hijack" gene programs evolved over millions of years to allow for feto-maternal tolerance in placental mammals in order to escape from immune vigilance and spread locally or to distant sites.

Placental immune editing switch (PIES): learning about immunomodulatory pathways from a unique case report.

The hypothesis of this work is that, in order to escape the natural immune surveillance mechanisms, cancer cells and the surrounding microenvironment might express ectopically genes that are physiologically present in the placenta to mediate fetal immune-tolerance. These natural "placental immune-editing switch" mechanisms (PIES) may represent the result of millions of years of mammalian evolution developed to allow materno-fetal tolerance. Here, we introduce genes of the immune regulatory pathways that are either similarly over- or under-expressed in tumor vs normal tissue. Our analysis was carried out in primary breast cancer with metastatic homolateral axillary lymph nodes as well as placenta tissue (both uterine decidual tissue and term placenta tissue) from a pregnant woman. Gene expression profiling of paired non-self and self tissues (i.e. placenta/uterus; breast cancer/normal breast tissue; metastatic lymphnode/normal lymphnode tissue) was performed using the PanCancer Immune gene panel, a 770 Nanostring gene expression panel. Our findings reveal overlapping in specific immune gene expression in placenta and cancer tissue, suggesting that these genes might play an important role in maintaining immune tolerance both physiologically (in the placenta) and pathologically (in the cancer setting).

The yin and yang of cancer therapeutics.

In this review, a potential theoretical framework for cancer therapeutics is presented, based on two concepts. The first concept considers cancer as a 'disease process' involving key regulatory pathways, and is discussed along with recent evidence and topics of special interest such as the combination of molecular diagnostics with developmental therapeutics. The second concept is the binary state concept of 'active/inactive' that seeks more relevant targets within the global molecular matrix of any given cancer. Here, these concepts are considered, along with the growing body of evidence that supports them. The 'binary' concept may facilitate both target selection and target validation.