Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial

Background: Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series. Patients and methods: KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post hoc, exploratory analysis. The main outcome measures were best overall response rate (complete response + partial response) and clinical benefit rate (complete response + partial response + stable disease lasting =6 months) by RECIST v1.1 criteria, progression-free survival, overall survival, and safety. Results: Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the best overall response rate and clinical benefit rate were 21.4% [95% confidence interval (CI) 14.6–29.6] and 42.9% (95% CI 34.1–52.0), respectively. A reduction in the sum of the major diameters of BM =30% occurred in 42.9% (95% CI 34.1–52.0), including 49.3% (95% CI 36.9–61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median progression-free survival and overall survival were 5.5 (95% CI 5.3–5.6) months and 18.9 (95% CI 17.1–21.3) months, respectively. The adverse event profile was broadly similar in patients with and without baseline BM, although nervous system adverse events were more common in patients with [208 (52.3%)] versus without [701 (43.7%)] baseline BM. Conclusion: This exploratory analysis of patients with HER2-positive metastatic breast cancer and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting

Ancient homeobox gene loss and the evolution of chordate brain and pharynx development: deductions from amphioxus gene expression

Homeobox genes encode a large superclass of transcription factors with widespread roles in animal development. Within chordates there are over 100 homeobox genes in the invertebrate cephalochordate amphioxus and over 200 in humans. Set against this general trend of increasing gene number in vertebrate evolution, some ancient homeobox genes that were present in the last common ancestor of chordates have been lost from vertebrates. Here, we describe the embryonic expression of four amphioxus descendants of these genes—AmphiNedxa, AmphiNedxb, AmphiMsxlx and AmphiNKx7. All four genes are expressed with a striking asymmetry about the left–right axis in the pharyngeal region of neurula embryos, mirroring the pronounced asymmetry of amphioxus embryogenesis. AmphiMsxlx and AmphiNKx7 are also transiently expressed in an anterior neural tube region destined to become the cerebral vesicle. These findings suggest significant rewiring of developmental gene regulatory networks occurred during chordate evolution, coincident with homeobox gene loss. We propose that loss of otherwise widely conserved genes is possible when these genes function in a confined role in development that is subsequently lost or significantly modified during evolution. In the case of these homeobox genes, we propose that this has occurred in relation to the evolution of the chordate pharynx and brain

Morphogenetic mechanisms forming the notochord rod: The turgor pressure‐sheath strength model

The notochord is a defining feature of chordates. During notochord formation in vertebrates and tunicates, notochord cells display dynamic morphogenetic movement, called convergent extension, in which cells intercalate and align at the dorsal midline. However, in cephalochordates, the most basal group of chordates, the notochord is formed without convergent extension. It is simply developed from mesodermal cells at the dorsal midline. This suggests that convergent extension movement of notochord cells is a secondarily acquired developmental attribute in the common ancestor of olfactores (vertebrates + tunicates), and that the chordate ancestor innovated the notochord upon a foundation of morphogenetic mechanisms independent of cell movement. Therefore, this review focuses on biological features specific to notochord cells, which have been well studied using clawed frogs, zebrafish, and tunicates. Attributes of notochord cells, such as vacuolation, membrane trafficking, extracellular matrix formation, and apoptosis, can be understood in terms of two properties: turgor pressure of vacuoles and strength of the notochord sheath. To maintain the straight rod-like structure of the notochord, these parameters must be counterbalanced. In the future, the turgor pressure-sheath strength model, proposed in this review, will be examined in light of quantitative molecular data and mathematical simulations, illuminating the evolutionary origin of the notochord