Clonal Evolution in Patients with Hormone Receptor Positive, HER-2 Negative Breast Cancer Treated with Chemotherapy or CDK4/6 Inhibitors.

INTRODUCTION: Somatic evolution of the cancer genome resulting in genetically different subclones is thought to be involved in the development of treatment resistance but might also offer new therapeutic opportunities in metastatic breast cancer. No data are available if clonal evolution differs in patients treated with chemotherapy (chemo) or CDK4/6 inhibitors given with endocrine treatment (CE treatment). METHODS: We performed a prospective analysis of circulating tumor DNA (ctDNA) by targeted next-generation sequencing in 46 patients before the beginning of a systemic first-line (n = 37) or second-line (n = 9) treatment. Ct DNA was analyzed again upon disease progression. RESULTS: New mutations in ctDNA of patients with progressive disease were detected in 1/11 patients who started chemo, in 4/9 patients treated with chemo followed by CE maintenance treatment, and in 9/26 patients receiving CE therapy. The number of acquired new mutations did not differ significantly between the three therapy cohorts (all p values >0.05). However, in patients classified as secondary resistant (n = 37), occurrence of new mutations significantly differed between patients who started chemo (0/9) compared to patients treated with chemo followed by CE (4/11; p = 0.041) and patients receiving CE therapy (8/19; p = 0.024), respectively. CONCLUSION: Clonal evolution might differ significantly between metastatic breast cancer patients with hormone receptor positive and HER-2 negative disease treated with chemo or CDK4/6 inhibitors. These results should be confirmed in larger patient cohorts.

Elective Discontinuation of CDK4/6 Inhibitors in Patients with Metastatic Hormone Receptor-Positive, Her-2-Negative Breast Cancer: A Retrospective Single-Center Experience.

INTRODUCTION: Cyclin-dependent 4/6 kinase (CDK4/6) inhibitors given with endocrine therapy until disease progression are standard of care in the treatment of women with advanced HR-positive Her-2-negative breast cancer. No data are available if therapy can be safely de-escalated to endocrine monotherapy in patients with long-lasting disease control. METHODS: We performed a retrospective analysis on the clinical course of 22 patients at our center who received CDK4/6 inhibitors with aromatase inhibitors or fulvestrant. All patients had at least stable disease for >6 months and made a joint decision with their provider to electively discontinue CDK4/6 inhibitors. Best objective response (BOR) at treatment discontinuation, progression-free survival, and re-treatment characteristics were recorded. RESULTS: Of 138 patients who received CDK4/6 inhibitors as first- or second-line therapy at our center, 22 met the inclusion criteria. Median duration of CDK4/6 treatment was 18 months (range 6-45). BOR was complete response in 1, partial response in 8, and stable disease in 13 patients. After a median duration of endocrine monotherapy of 9.5 months (range 5-44 months), 6 of 22 patients had progressive disease (1 local relapse and 5 systemic progression). All patients with disease progression had at least stable disease to chemotherapy (N = 1) or re-treatment with CDK4/6 inhibitors (N = 4). CONCLUSION: Elective discontinuation of CDK4/6 inhibitors is feasible in patients with long-lasting disease stabilization. This strategy should be evaluated in prospective trials.

Mucormycosis treated with posaconazole: review of 96 case reports.

Mucormycosis is an emerging invasive fungal infection, primarily affecting immunocompromised patients. The disease is difficult to diagnose and mortality reaches 40% even if treated adequately. Depending on site of infection and risk factors, surgical debridement in combination with systemically active antifungal drugs are the mainstay treatment strategies. Lipid-based amphotericin B is the treatment of choice for first-line therapy while posaconazole may be a promising alternative. We performed a PubMed search on reports of patients with mucormycosis treated with posaconazole. From 2003 to 2011, 96 cases have been published. Diagnosis was based on histology alone in 2 (2.1%) and microbiological evidence in 67 (69.8%), while no data on the diagnostic approach was reported in 27 (28.1%) patients. The most frequent pathogens were Rhizopus spp. (31.2%), followed by Mucor spp. (14.6%). The site of infection was predominantly rhino-orbital (38.5%, of which 43% also had central nervous system [CNS] involvement), followed by disseminated disease (22.1%). A complete response was achieved in 62 (64.6%), partial response in 7 (7.3%) patients, and stable disease in 1 (1%). Overall mortality was 24% (lacking data for three patients). In published case reports on posaconazole treatment for mucormycosis, the drug was frequently and successfully used in combination or as second line therapy.