Subphenotypes of mild-to-moderate COPD by factor and cluster analysis of pulmonary function, CT imaging and breathomics in a population-based survey.

INTRODUCTION: Classification of COPD is currently based on the presence and severity of airways obstruction. However, this may not fully reflect the phenotypic heterogeneity of COPD in the (ex-) smoking community. We hypothesized that factor analysis followed by cluster analysis of functional, clinical, radiological and exhaled breath metabolomic features identifies subphenotypes of COPD in a community-based population of heavy (ex-) smokers. METHODS: Adults between 50-75 years with a smoking history of at least 15 pack-years derived from a random population-based survey as part of the NELSON study underwent detailed assessment of pulmonary function, chest CT scanning, questionnaires and exhaled breath molecular profiling using an electronic nose. Factor and cluster analyses were performed on the subgroup of subjects fulfilling the GOLD criteria for COPD (post-BD FEV1/FVC < 0.70). RESULTS: Three hundred subjects were recruited, of which 157 fulfilled the criteria for COPD and were included in the factor and cluster analysis. Four clusters were identified: cluster 1 (n = 35; 22%): mild COPD, limited symptoms and good quality of life. Cluster 2 (n = 48; 31%): low lung function, combined emphysema and chronic bronchitis and a distinct breath molecular profile. Cluster 3 (n = 60; 38%): emphysema predominant COPD with preserved lung function. Cluster 4 (n = 14; 9%): highly symptomatic COPD with mildly impaired lung function. In a leave-one-out validation analysis an accuracy of 97.4% was reached. CONCLUSIONS: This unbiased taxonomy for mild to moderate COPD reinforces clusters found in previous studies and thereby allows better phenotyping of COPD in the general (ex-) smoking population.

Daily Oral Ibandronate With Adjuvant Endocrine Therapy in Postmenopausal Women With Estrogen Receptor-Positive Breast Cancer (BOOG 2006-04): Randomized Phase III TEAM-IIB Trial.

PURPOSE: For postmenopausal patients with breast cancer, previous subgroup analyses have shown a modest benefit from adjuvant bisphosphonate treatment. However, the efficacy of oral nitrogen-containing bisphosphonates such as ibandronate is unclear in this setting. TEAM-IIB investigates adjuvant ibandronate in postmenopausal women with estrogen receptor-positive (ER+) breast cancer. METHODS: TEAM-IIB is a randomized, open-label, multicenter phase III study. Postmenopausal women with stage I-III ER+ breast cancer and an indication for adjuvant endocrine therapy (ET) were randomly assigned 1:1 to 5 years of ET with or without oral ibandronate 50 mg once daily for 3 years. Major ineligibility criteria were bilateral breast cancer, active gastroesophageal problems, and health conditions that might interfere with study treatment. Primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population. RESULTS: Between February 1, 2007, and May 27, 2014, 1,116 patients were enrolled, 565 to ET with ibandronate (ibandronate arm) and 551 to ET alone (control arm). Median follow-up was 8.5 years. DFS was not significantly different between the ibandronate and control arms (HR, 0.97; 95% CI, 0.76 to 1.24; log-rank P = .811). Three years after random assignment, DFS was 94% in the ibandronate arm and 91% in the control arm. Five years after random assignment, this was 89% and 86%, respectively. In the ibandronate arm, 97/565 (17%) of patients stopped ibandronate early because of adverse events. Significantly more patients experienced GI issues, mainly dyspepsia, in the ibandronate arm than in the control arm (89 [16%] and 54 [10%], respectively; P < .003). Eleven patients in the ibandronate arm developed osteonecrosis of the jaw. CONCLUSION: In postmenopausal women with ER+ breast cancer, adjuvant ibandronate 50 mg once daily does not improve DFS and should not be recommended as part of standard treatment regimens.

Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments.

PURPOSE: Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types. EXPERIMENTAL DESIGN: Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available. RESULTS: This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types. CONCLUSIONS: From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.

Carboplatin-Cyclophosphamide or Paclitaxel without or with Bevacizumab as First-Line Treatment for Metastatic Triple-Negative Breast Cancer (BOOG 2013-01).

BACKGROUND: The addition of bevacizumab to chemotherapy conferred a modest progression-free survival (PFS) benefit in metastatic triple-negative breast cancer (mTNBC). However, no overall survival (OS) benefit has been reported. Also, its combination with carboplatin-cyclophosphamide (CC) has never been investigated. METHODS: The Triple-B study is a multicenter, randomized phase IIb trial that aims to prospectively validate predictive biomarkers, including baseline plasma vascular endothelial growth factor receptor-2 (pVEGFR-2), for bevacizumab benefit. mTNBC patients were randomized between CC and paclitaxel (P) without or with bevacizumab (CC ± B or P ± B). Here we report on a preplanned safety and preliminary efficacy analysis after the first 12 patients had been treated with CC+B and on the predictive value of pVEGFR-2. RESULTS: In 58 patients, the median follow-up was 22.1 months. Toxicity was manageable and consistent with what was known for each agent separately. There was a trend toward a prolonged PFS with bevacizumab compared to chemotherapy only (7.0 vs. 5.2 months; adjusted HR = 0.60; 95% CI 0.33-1.08; p = 0.09), but there was no effect on OS. In this small study, pVEGFR-2 concentration did not predict a bevacizumab PFS benefit. Both the intention-to-treat analysis and the per-protocol analysis did not yield a significant treatment-by-biomarker test for interaction (pinteraction = 0.69). CONCLUSIONS: CC and CC+B are safe first-line regimens for mTNBC and the side effects are consistent with those known for each individual agent. pVEGFR-2 concentration did not predict a bevacizumab PFS benefit.

POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined with Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients.

PURPOSE: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)-positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform-sparing PI3 kinase inhibitor. PATIENTS AND METHODS: 30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a "rolling six" design. RESULTS: Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients. CONCLUSIONS: Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.

Independent replication of polymorphisms predicting toxicity in breast cancer patients randomized between dose-dense and docetaxel-containing adjuvant chemotherapy.

INTRODUCTION: Although pharmacogenomics has evolved substantially, a predictive test for chemotherapy toxicity is still lacking. We compared the toxicity of adjuvant dose-dense doxorubicin-cyclophosphamide (ddAC) and docetaxel-doxorubicin-cyclophosphamide (TAC) in a randomized multicenter phase III trial and replicated previously reported associations between genotypes and toxicity. RESULTS: 646 patients (97%) were evaluable for toxicity (grade 2 and higher). Whereas AN was more frequent after ddAC (P < 0.001), TAC treated patients more often had PNP (P < 0.001). We could replicate 2 previously reported associations: TECTA (rs1829; OR 4.18, 95% CI 1.84-9.51, P = 0.001) with PNP, and GSTP1 (rs1138272; OR 2.04, 95% CI 1.13-3.68, P = 0.018) with PNP. MATERIALS AND METHODS: Patients with pT1-3, pN0-3 breast cancer were randomized between six cycles A60C600 every 2 weeks or T75A50C500 every 3 weeks. Associations of 13 previously reported single nucleotide polymorphisms (SNPs) with the most frequent toxicities: anemia (AN), febrile neutropenia (FN) and peripheral neuropathy (PNP) were analyzed using logistic regression models. CONCLUSIONS: In this independent replication, we could replicate an association between 2 out of 13 SNPs and chemotherapy toxicities. These results warrant further validation in order to enable tailored treatment for breast cancer patients.