cabozantinib and Breast-Neoplasms

To analyze the efficacy and tolerability of cabozantinib-a small molecule inhibitor of MET and VEGFR2-alone or with trastuzumab in patients with breast cancer brain metastases (BCBM).. This single-arm phase II study enrolled patients with new or progressive measurable BCBM into 3 cohorts: Cohort 1 (HER2-positive), Cohort 2 (hormone receptor-positive/HER2-negative), and Cohort 3 (triple-negative). Patients received cabozantinib 60-mg daily on a 21-day cycle. Cohort 1 added trastuzumab every 3 weeks and had a primary objective of central nervous system (CNS) objective response rate (ORR) by RECIST 1.1. Secondary objectives for all cohorts were progression-free survival, overall survival, toxicity, and changes in vascular parameters and circulating biomarkers. Cohorts 2 and 3 also had CNS ORR as a secondary objective.. Thirty-six BCBM patients enrolled (cohort 1, n = 21; cohort 2, n = 7; cohort 3, n = 8), with a median age of 50. Patients had a median of 3 prior lines for metastatic disease (range 1-9). Treatments prior to enrollment included craniotomy (n = 4), whole brain radiation (n = 24) and stereotactic radiosurgery (n = 11). CNS ORR was 5% in cohort 1, 14% in cohort 2, and 0% in cohort 3. Most common grade 3/4 adverse events included elevations in lipase (11%), AST (8%), ALT (6%), hyponatremia (8%), and hypertension (6%). Cabozantinib increased plasma concentrations of CA-IX, soluble (s)MET, PlGF, sTIE-2, VEGF, and VEGF-D, and decreased sVEGFR2 and TNF-α and total tumor blood volume.. Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia.. Clinicaltrial.gov registration: NCT02260531.

Topics: Adult; Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Breast Neoplasms; Cohort Studies; Drug Administration Schedule; Female; Humans; Middle Aged; Pyridines; Receptor, ErbB-2; Survival Analysis; Trastuzumab; Treatment Outcome; Young Adult

We assessed the antitumor activity of cabozantinib, a potent multireceptor oral tyrosine kinase inhibitor, in patients with hormone receptor-positive breast cancer with bone metastases.. In this single-arm multicenter phase II study, patients received an initial starting dose of 100 mg, later reduced to 60 mg, per day. The primary endpoint was the bone scan response rate. Secondary endpoints included objective response rate by RECIST, progression-free survival (PFS), and overall survival (OS).. Of 52 women enrolled, 20 (38%) experienced a partial response on bone scan and 6 (12%) had stable disease. Prior to the first repeat bone scan at 12 weeks, 19 (35%) patients discontinued study treatment because of early clinical progression or unacceptable toxicity. RECIST evaluation based on best overall response by computed tomography revealed stable disease in extraosseous tissues in 26 patients (50%) but no complete or partial responses. In 25 patients with disease control on bone scan at 12 weeks, only 3 (12%) patients developed extraosseous progression. The median PFS was 4.3 months, and median OS was 19.6 months. The most common grade 3 or 4 toxicities were hypertension (10%), anorexia (6%), diarrhea (6%), fatigue (4%), and hypophosphatemia (4%).. Bone scans improved in 38% of patients with metastatic hormone receptor-positive breast cancer and remained stable in an additional 12% for a minimum duration of 12 weeks on cabozantinib. Further investigations should assess the activity of cabozantinib in combination with other hormonal and other breast cancer therapies and determine whether bone scan responses correlate with meaningful antitumor effects. ClinicalTrials.gov identifier. NCT01441947 IMPLICATIONS FOR PRACTICE: Most patients with metastatic hormone receptor-positive (HR+) breast cancer have bone involvement, and many have bone-only disease, which is difficult to evaluate for response. This phase II single-arm study evaluated the clinical activity of the small molecule MET/RET/VEGFR2 inhibitor cabozantinib in patients with metastatic HR+ breast cancer with bone metastases. This study met its primary endpoint, and cabozantinib treatment resulted in a significant bone scan response rate correlating with improved survival. This is the first study to use bone scan response as a primary endpoint in breast cancer. The results support further study of cabozantinib in HR+ breast cancer.

Topics: Anilides; Breast Neoplasms; Female; Hormones; Humans; Pyridines

Cabozantinib (XL184), a multi-targeted oral tyrosine kinase inhibitor with activity against MET, VEGFR2, AXL, and other tyrosine kinases, was assessed in a cohort of metastatic breast cancer (MBC) patients in a phase II randomized discontinuation trial (RDT).. Patients received 100 mg cabozantinib daily during a 12-week lead-in stage. Those with stable disease per modified Response Evaluation Criteria in Solid Tumors version 1.0 at 12 weeks were randomized to either continue cabozantinib or receive placebo. Primary endpoints were objective response rate (ORR) during the 12-week lead-in stage and progression-free survival (PFS) after randomization. Patients were also followed for overall survival (OS).. Forty-five patients with MBC and a median of three prior lines of chemotherapy for metastatic disease were enrolled. The ORR during the lead-in stage was 13.6 % (95 % confidence interval [CI] 6-25.7 %), and the disease control rate at week 12 was 46.7 % (95 % CI 31.7-61.6 %). Per the initial RDT study design, patients with stable disease at week 12 were randomized to cabozantinib or placebo. Following a Study Oversight Committee recommendation, randomization was suspended. Patients in the lead-in stage continued on open-label cabozantinib. Patients in the randomization stage were subsequently unblinded. The overall median PFS for all MBC patients was 4.3 months. Median OS was 11.4 months (95 % CI 10.5-16.5 months). The most common grade 3/4 adverse events in the lead-in stage were palmar-plantar erythrodysesthesia (13 %) and fatigue (11 %). One death from respiratory failure was reported as drug-related during the lead-in stage.. In heavily pretreated MBC patients, cabozantinib monotherapy demonstrated clinical activity including objective response and disease control.

Topics: Adult; Aged; Anilides; Antineoplastic Agents; Biopsy; Breast Neoplasms; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Protein Kinase Inhibitors; Pyridines; Survival Analysis; Tomography, X-Ray Computed; Treatment Outcome

The genesis of all cancers results from an accumulation of mutations, constitutional and/or acquired when induced by external mutagenic factors. High-speed technologies for genome sequencing have completely changed the study of disease genetics, but with limited knowledge of the functional value of most genetic changes.. Here, we proposed an innovative individual approach by studying tissue samples from a young woman with an unusual association of breast cancer, polycythemia vera, and rheumatoid arthritis. We performed genomic analyses for copy number variations and point mutations on laser-microdissected tumor cells from the breast cancer, and on CD34. Using ONCOSCAN technology, we identified a constitutional pR988C, c2962C>T mutation of. Our study opens a considerable field of application in the domain of constitutional genetics, to establish genetic links between cancers and other very different severe diseases.

Topics: Adult; Anilides; Animals; Arthritis, Rheumatoid; Autoimmune Diseases; Breast Neoplasms; Carcinoma, Squamous Cell; Chronic Disease; Female; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Myeloproliferative Disorders; Polycythemia Vera; Proto-Oncogene Proteins c-met; Pyridines; Skin Neoplasms

Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions (NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers.

Topics: Anilides; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mice; Mice, Nude; Mitogen-Activated Protein Kinases; NIH 3T3 Cells; Nuclear Receptor Coactivators; Oncogene Proteins, Fusion; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; ras Guanine Nucleotide Exchange Factors; Receptor, ErbB-2; Signal Transduction; Xenograft Model Antitumor Assays

Topics: Aminopyridines; Anilides; Animals; Antineoplastic Agents; Apoptosis; Breast; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cyclin-Dependent Kinase 9; Drug Screening Assays, Antitumor; Female; Humans; Lung; Lung Neoplasms; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Protein Kinase Inhibitors; Purines; Pyridines