Background: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. Patients and methods: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for !5 years AE abemaciclib for 2 years. Cohort 1 enrolled patients with !4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor !5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (!20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. Results: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib þ ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) ¼ 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P ¼ 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR ¼ 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR ¼ 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. Conclusion: Abemaciclib þ ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

No abstract

Tumor acidity is one of the cancer hallmarks and is associated with metabolic reprogramming and the use of glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid acid stress major by the activation and expression of proton and lactate transporters and exchangers and have an inverted pH gradient (extracellular and intracellular pHs are acid and alkaline, respectively). The shift in the tumor acid–base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, and treatment resistance. For example, weak-base chemotherapeutic agents may have a substantially reduced cellular uptake capacity due to “ion trapping”. Lactic acid negatively affects the functions of activated effector T cells, stimulates regulatory T cells, and promotes them to express programmed cell death receptor 1. On the other hand, the inversion of pH gradient could be a cancer weakness that will allow the development of new promising therapies, such as tumor-targeted pH-sensitive antibodies and pH-responsible nanoparticle conjugates with anticancer drugs. The regulation of tumor pH levels by pharmacological inhibition of pH-responsible proteins (monocarboxylate transporters, H+-ATPase, etc.) and lactate dehydrogenase A is also a promising anticancer strategy. Another idea is the oral or parenteral use of buffer systems, such as sodium bicarbonate, to neutralize tumor acidity. Buffering therapy does not counteract standard treatment methods and can be used in combination to increase effectiveness. However, the mechanisms of the anticancer effect of buffering therapy are still unclear, and more research is needed. We have attempted to summarize the basic knowledge about tumor acidity.

No abstract

Sensitivity of gastric cancer (GC) to conventional cytotoxic therapy may be at least in part attributed to molecular features of the tumor cells. We analyzed all patients with metastatic GC treated in the N.N. Petrov Institute of Oncology (St. Petersburg) within years 1999-2010 and identified 65 cases with evaluable treatment response and available biological material. Two of 65 patients (3 %) carried germ-line BRCA1 5382insC mutation and demonstrated particularly pronounced response to the treatment; both of their tumors showed loss of the remaining BRCA1 allele, thus confirming the causative role of BRCA1 heterozygosity in GC predisposition. RNA expression of TS, DPD, BRCA1, ERCC, TOP2A and bTUBIII was analyzed in the remaining 63 tumors. Low BRCA1 expression was associated with increased response rate [6/9 (67 %) vs. 17/54 (32 %), p = 0.04]. Low bTUBIII level correlated with the improved probability of tumor response [21/49 (43 %) vs. 1/13 (8 %), p = 0.02] and prolonged overall survival (10.5 vs. 7.1 months, p = 0.02); this trend was maintained both for taxane-containing and for taxane-free drug combinations. We conclude that GC should be considered as a part of BRCA1-related hereditary cancer syndrome. Tumors with BRCA1 inactivation and low bTUBIII expression demonstrate improved response to cytotoxic therapy.