Olivier Trédan

Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

Lymphopenia is frequent in advanced cancers and predicts the toxicity of chemotherapy. Its effect on relapse and survival is uncertain. Its prognostic value for survival was analyzed in three databases of previously reported prospective multicenter studies: (a) FEC chemotherapy in metastatic breast carcinoma; (b) CYVADIC in advanced soft tissue sarcoma (European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group 62791); and (c) prospective, consecutive phase III studies of aggressive diffuse large-cell non-Hodgkin's lymphomas conducted at Centre Léon Bérard between 1987 and 1993. Univariate and multivariate analyses of prognostic factors for survival were performed. The incidence of lymphopenia of <1,000/microL before treatment was constant among the series: 25%, 24%, and 27%, respectively. Lymphopenia was significantly more frequent (P < 0.05) in metastatic breast cancer patients with performance status (PS) of >1, non-Hodgkin's lymphoma patients with international prognostic index (IPI) of > 0, and advanced soft tissue sarcoma and metastatic breast cancer patients with bone metastases. Inunivariate analysis, lymphopenia of <1,000/microL significantly correlated to overall survival in patients with metastatic breast cancer (median, 10 versus 14 mo; P < 0.0001), advanced soft tissue sarcoma (median, 5 versus 10 months; P < 0.01), and non-Hodgkin lymphoma (median, 11 versus 94 months; P < 0.0001). In multivariate analysis (Cox model), lymphopenia was an independent prognostic factor for overall survival in metastatic breast cancer [RR (relative risk), 1.8; 95% CI (confidence interval), 1.3-2.4] along with liver metastases and PS; in advanced soft tissue sarcoma (RR, 1.46; 95% CI, 1.0-2.1) along with liver metastases, lung metastases, and PS; and in non-Hodgkin's lymphoma (RR, 1.48; 95% CI, 1.03-2.1) along with IPI. Our findings show that lymphopenia is an independent prognostic factor for overall and progression-free survival in several cancers.