The exciting new field of her2-low breast cancer treatment

Since human epidermal growth factor receptor-2 (HER2) characterization, going through clinical research and regulatory approval of HER2-targeted therapies, much has elapsed and is still unfolding. Hitherto, only breast cancer (BC) patients with HER2 immunohistochemistry 3+ or with HER2 gene fluorescence in-situ hybridization (FISH) amplification (a.k.a. HER2-positive BC) have benefited from anti-HER2 agents. In recent years, however, much of the research effort has been expanded, with positive outcomes being reached for formerly known HER2-negative BC that yet express HER2 to some degree (HER2 immunohistochemistry 1+ or 2+, but FISH negative) and are currently being classified as HER2-low BC for the purpose of trial enrollment. In this sense, our aim is to review the body of evidence of HER2-low BC that led to the study of first-generation anti-HER2 agents, like trastuzumab, and how they have failed to achieve any clinical applicability in this setting. In addition, we review new data that is leading to the growing success of the new generation of drugs, especially the promising HER2-directed antibody–drug conjugates. A narrative review is also performed regarding the rationale behind the consolidated and ongoing clinical trials studying anti-HER2 agents in combination with unrelated agents, such as immunotherapy, endocrine therapy, and CDK4/6 inhibitors. Hopefully, all this ongoing research effort will be able to extend the survival benefits seen with anti-HER2 agents in HER2-positive disease, at least to some degree, to the greater proportion of patients with HER2-low BC.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets

Introduction Triple-negative breast cancer (TNBC) is considered the most aggressive breast cancer subtype with the least favorable outcomes. However, recent research efforts have generated an enhanced knowledge of the biology of the disease and have provided a new, more comprehensive understanding of the multifaceted ecosystem that underpins TNBC. Areas covered In this review, the authors illustrate the principal biological characteristics of TNBC, the molecular driver alterations, targetable genes, and the biomarkers of immune engagement that have been identified across the subgroups of TNBC. Accordingly, the authors summarize the landscape of the innovative and investigative biomarker-driven therapeutic options in TNBC that emerge from the unique biological basis of the disease. Expert opinion The therapeutic setting of TNBC is rapidly evolving. An enriched understanding of the tumor spatial and temporal heterogeneity and the surrounding microenvironment of this complex disease can effectively support the development of novel and tailored opportunities of treatment

Tetrakis(thiadiazole)porphyrazines. 4. Direct Template Synthesis, Structure, General Physicochemical Behavior, and Redox Properties of A(lIII), Ga(III), and In(III) Complexes

Monometallic derivatives of tetrakis(1,2,5-thiadiazole)porphyrazine, [TTDPzH2], with main group tervalent metal ions having the formulae [TTDPzMX] (TTDPz = tetrakis(1,2,5-thiadiazole)porphyrazinato dianion; M = AlIII, X = Cl-, Br-, OH-; M = GaIII, X = Cl-, OH-; M = InIII, X = AcO-) were prepared and investigated by single-crystal X-ray analysis and IR and UV−vis spectroscopy as well as cyclic voltammetry and spectroelectrochemistry. The complexes [TTDPzMX] (M = AlIII, X = Cl-, Br-; M = GaIII, X = Cl-) were obtained by direct autocyclotetramerization of the precursor 3,4-dicyano-1,2,5-thiadiazole in hot quinoline in the presence of MX3 salts (M = AlIII, GaIII; X = Cl-, Br-) and were hydrolized to form the corresponding hydroxide derivatives, [TTDPzMOH]. The InIII complex, [TTDPzIn(OAc)], was obtained from the free-base macrocycle [TTDPzH2] with In(OH)(OAc)2 in CH3COOH. A single-crystal X-ray study was made at 173 K on the two isostructural species [TTDPzMCl] (M = AlIII, GaIII), which have space group P, with a = 12.470(14), b = 12.464(13), and c = 13.947(12) Å, α = 70.72(3), β = 79.76(3), and γ = 90.06(3)°, V = 2009.3(3) Å3, and Z = 4 for [TTDPzAlCl] and a = 12.429(3), b = 12.430(3), and c = 13.851(3) Å, α = 70.663(6), β = 79.788(8), and γ = 89.991(9)°, V = 1983.3(7) Å3, and Z = 4 for [TTDPzGaCl]. Square pyramidal coordination exists about the MIII centers, with Cl- occupying the apical position (Al−Cl = 2.171(5) and Ga−Cl = 2.193(1) Å). AlIII and GaIII are located at distances of 0.416(6) and 0.444(2) Å from the center of the N4 system. The molecular packing consists of stacked double layers with internal and external average interlayer distances of 3.2 and 3.3 Å, respectively. IR spectra show ν(Al−Cl) at 345 cm-1 for [TTDPzAlCl], ν(Al−Br) at 330 cm-1 for [TTDPzAlBr], and ν(Ga−Cl) at 382 cm-1 for [TTDPzGaCl]. The UV−vis spectra in weakly basic (pyridine, DMF, DMSO) and acidic solvents (CF3COOH, H2SO4) show the typical intense π → π* transition bands in the Soret (300−400 nm) and Q-band regions (640−660 nm), the bands evidencing some dependence on the nature of the solvent, particularly in acidic solutions. Cyclic voltammetry, differential pulse voltammetry, and thin-layer spectroelectrochemical measurements in pyridine and dimethylformamide of the species [TTDPzMX] indicate reversible first and second one-electron reductions, whereas additional ill-defined reductions are observed at more negative potentials. The examined species are much easier to reduce than their phthalocyanine or porphyrin analogues as a result of the remarkable electron-attracting properties of the TTDPz macrocycle which contains annulated strongly electron-deficient thiadiazole rings

Patterns of treatment and outcome of palbociclib plus endocrine therapy in hormone receptor-positive/HER2 receptor-negative metastatic breast cancer: a real-world multicentre Italian study

Background: The CDK4/6 inhibitor palbociclib combined with endocrine therapy (ET) has proven to prolong progression-free survival (PFS) in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). Few data are available regarding the efficacy of such a regimen outside the clinical trials. Patients and methods: This is a multicentre prospective real-world experience aimed at verifying the outcome of palbociclib plus ET in an unselected population of MBC patients. The primary aim was the clinical benefit rate (CBR); secondary aims were the median PFS, overall survival (OS) and safety. Patients received palbociclib plus letrozole 2.5 mg (cohort A) or fulvestrant 500 mg (cohort B). Results: In total, 191 patients (92 in cohort A, 99 in cohort B) were enrolled and treated, and 182 were evaluable for the analysis. Median age was 62 years (range 47–79); 54% had visceral involvement; 28% of patients had previously performed one treatment line (including chemotherapy and ET), 22.6% two lines and 15.9% three. An overall response rate of 34.6% was observed with 11 (6.0%) complete responses and 52 (28.6%) partial responses. Stable disease was achieved by 78 patients (42.9%) with an overall CBR of 59.8%. At a median follow-up of 24 months (range 6–32), median PFS was 13 months without significant differences between the cohorts. When analysed according to treatment line, PFS values were significantly prolonged when palbociclib-based therapy was administered as first-line treatment (14.0 months), to decrease progressively in second and subsequent lines (11.7 and 6.7 months, respectively). Median OS was 25 months, ranging from 28.0 months in 1st line to 18.0 and 13.0 months in 2nd and subsequent lines, respectively. Conclusions: Our data indicate that palbociclib plus ET is active and safe in HR+/HER2− MBC, also suggesting a better performance of the combinations in earlier treatment lines