Oral Abundance of Actinomyces spp. in Breast Cancer Patients.

OBJECTIVES: Pathophysiology of medication-related osteonecrosis of the jaw (MRONJ) is still unclear, and disease development is associated with adverse reaction of bisphosphonates and denosumab, and Actinomyces spp. as well. In this study, we evaluated the abundance of Actinomyces spp. in breast cancer patients undergoing chemotherapy compared to healthy controls. METHODS: Oropharyngeal samples were collected from treatment-naive early-stage breast cancer patients, who were scheduled for standard of care therapy (eight samples throughout chemotherapy, one prior to radiotherapy and one after a year of start), as well as from healthy controls at matched timepoints. We quantified Actinomyces spp. in the samples with a highly sensitive and specific quantitative polymerase chain reaction. RESULTS: Twenty-one patients and 16 healthy subjects were enrolled. Forty-eight percent of patients suffered from estrogen receptor-positive/progesterone receptor-positive or -negative/human epidermal growth factor receptor 2 (HER2)-negative disease, 38% were HER2-positive, and 14% were triple-negative. Comparison of Actinomyces spp. loads in cancer patients and healthy controls did not reveal significant difference. Fluctuations on bacterial quantity were observed in both groups over time. Tumor receptor status or different chemotherapy schemes of patients were not correlated with a particular pattern on abundance of Actinomyces spp. CONCLUSIONS: We suggest that Actinomyces spp. are not the initiative factors in MRONJ development. These bacteria are not altered in abundance during chemotherapy, but they behave opportunistic when there is a bone disruption in the oropharynx in the first place caused by antiresorptive drugs or dental trauma and proliferate in their new niche. Thus, Actinomyces spp. plays a latter role in MRONJ development, rather than a primary causative one.

Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported. METHODS: Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005-005275-15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58-95), 240 (14·0%) patients in the denosumab and 287 (16·8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0·82, 95% CI 0·69-0·98, Cox p=0·0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89·2% (95% CI 87·6-90·8) at 5 years and 80·6% (78·1-83·1) at 8 years of follow-up, compared with 87·3% (85·7-89·0) at 5 years and 77·5% (74·8-80·2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3·6%] of 1709 in the denosumab group vs 58 [3·4%] of 1690 in the placebo group), meniscus injury (23 [1·3%] vs 24 [1·4%]), and cataract (16 [0·9%] vs 28 [1·7%]). One (<0·1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group. INTERPRETATION: Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy. FUNDING: Amgen.

Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. METHODS: In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. INTERPRETATION: Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. FUNDING: Amgen.

Prophylactic long-acting granulocyte-colony stimulating factors (G-CSF) in gynecologic malignancies: an oncologic expert statement.

We reviewed the status of the use of the prophylactic long-acting granulocyte colony-stimulating factors (G-CSFs) pegfilgrastim and lipegfilgrastim in gynecologic malignancies. Long-acting G-CSFs should not be used in weekly regimens. Filgrastim is not indicated in patients with febrile and/or severe neutropenia after administration of long-acting G-CSF in the same cycle. One study has shown a moderate effect on febrile neutropenia of ciprofloxacin when co-administered with pegfilgrastim. There is broad evidence from meta-analyses that pegfilgrastim effectively reduces severe neutropenia. In parallel, its adverse effects have been studied extensively. All-cause mortality was significantly reduced by pegfilgrastim. The glycopegylated long-acting G-CSF, lipegfilgrastim has demonstrated antineutropenic efficacy similar to that of pegfilgrastimin in one breast cancer study. In another pivitol non-small cell lung cancer study, impaired survival was observed in the lipegfilgrastim group during the first 30 days of study. The European Medicines Agency claimed more profound safety data to be provided for lipegfilgrastim by 2017.

Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies. METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L. RESULTS: 563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed. CONCLUSIONS: These complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective. GOV REGISTRATION NUMBER: NCT02400476.