A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient.

After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.

A practical approach to aid physician interpretation of clinically actionable predictive biomarker results in a multi-platform tumor profiling service.

Patients in whom the standard of care has failed or who have uncommon tumors for which no standard of care exists are often treated with drugs selected based on the physician's best guess. The rate of success for this method is generally low. With the advent of fast, affordable tumor profiling technologies, and a growth in the understanding of predictive biomarkers, it is now possible to identify drugs potentially associated with clinical benefit for such patients. We present the Caris approach to evidence-based tumor profiling and two patients with advanced ovarian and prostate cancer in whom standard of care had failed and tumor profiling identified an effective treatment schedule. To establish Caris Molecular Intelligence(TM) (CMI), over 120,000 clinical publications were screened and graded to characterize the predictive value of biomarkers that form the panel of tests. CMI includes multiple technologies to measure changes in proteins, ribonucleic acid, and deoxyribonucleic acid and proprietary software that matches the test results with the published evidence. The CMI results enable physicians to select drugs that are more likely to benefit the patients, avoid drugs that are not likely to work, and find treatment options that otherwise would not be considered. Worldwide, over 60,000 cancer patients have undergone evidence-based tumor profiling with CMI. In the cases reported in this article, CMI identified treatments that would not have been routinely used in the respective clinical setting. The clinical outcomes observed help to illustrate the utility of this approach.

A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma.

The purpose of this study was to assess the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab (10 mg/kg q2w) plus cetuximab (400/250 mg/m(2) initial/weekly), either with (Arm A) or without (Arm B) gemcitabine (1000 mg/m(2) weekly × 3 of 4 weeks). Tumor assessments were performed q8w. Primary study endpoint was progression-free survival (PFS). Sixty-one patients were randomized to Arm A (n = 30) or Arm B (n = 31). Median treatment duration was 9 weeks in Arm A and 8 weeks in Arm B (range, 2.0-40.4). Patients in Arm A had median PFS and overall survival values of 3.55 months and 5.41 months, respectively, compared to 1.91 months and 4.17 months in Arm B. The study closed early due to lack of sufficient efficacy in both treatment arms. Although both regimens were well tolerated, patients treated with gemcitabine experienced more grade 3-4 toxicities, including proteinuria and thromboembolic events. The combination of cetuximab and bevacizumab did not result in promising activity with or without gemcitabine, suggesting that a strategy of dual EGFR/VEGF inhibition in pancreatic cancer does not warrant further development. To our knowledge, this is one of the first trials to evaluate a completely noncytotoxic regimen in the first-line treatment of advanced pancreatic cancer. (ClinicalTrials.gov number, NCT00326911).

Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck.

PURPOSE: This multicenter phase II study was undertaken to define the efficacy and safety of cetuximab, an antiepidermal growth factor receptor chimeric human and murine monoclonal antibody, administered with cisplatin to patients with refractory metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: One hundred thirty-two patients were to receive two 3-week cycles with cisplatin/paclitaxel or cisplatin/fluorouracil. Patients (n = 30) with a complete or partial response continued standard therapy. Seventy-six patients with stable disease (SD; n = 51) or progressive disease (PD/1; n = 25) received combination therapy with cetuximab (400 mg/m2 intravenously on day 1, then 250 mg/m2/wk) and cisplatin (75 or 100 mg/m2 intravenously on day 1 every 3 weeks). The protocol was subsequently amended to enroll patients who had developed PD within 90 days after platinum-based therapy (PD/2; n = 54). RESULTS: Five patients (20%) in PD/1, three patients (6%) in PD/2, and nine patients (18%) with SD achieved an objective response. Median duration of response was 4.2, 4.1, and 7.4 months for the PD/1, PD/2, and SD groups, respectively, with median overall survival times of 6.1, 4.3, and 11.7 months. The most common toxicities were anemia, acne-like skin rash, leukopenia, fatigue and malaise, and nausea and vomiting. Seven patients (5%) developed a grade 3 or 4 hypersensitivity reaction to cetuximab. CONCLUSION: Cetuximab and cisplatin is an active regimen in refractory SCCHN. The relative contribution of cetuximab is better defined in a single-agent trial. Cetuximab did not exacerbate cisplatin toxicity but was associated with skin rash in a majority of patients and occasional serious allergic reactions. Further study of this compound is warranted.

Robotically guided radiosurgery for children.

BACKGROUND: A robotically guided linear accelerator has recently been developed which provides frameless radiosurgery with high precision. Potential advantages for the pediatric population include the avoidance of the cognitive decline associated with whole brain radiotherapy, the ability to treat young children with thin skulls unsuitable for frame-based methods, and the possible avoidance of general anesthesia. We report our experience with this system (the "Cyberknife") in the treatment of 21 children. PROCEDURES: Cyberknife radiosurgery was performed on 38 occasions for 21 patients, age ranging from 8 months to 16 years (7.0 +/- 5.1 years), with tumors considered unresectable. Three had pilocytic astrocytomas, two had anaplastic astrocytomas, three had ependymomas (two anaplastic), four had medulloblastomas, three had atypical teratoid/rhabdoid tumors, three had craniopharyngiomas, and three had other pathologies. The mean target volume was 10.7 +/- 20 cm(3), mean marginal dose was 18.8 +/- 8.1 Gy, and mean follow-up is 18 +/- 11 months. Twenty-seven (71%) of the treatments were single-shot and eight (38%) patients did not require general anesthesia. RESULTS: Local control was achieved in the patients with pilocytic and anaplastic astrocytoma, three of the patients with medulloblastoma, and the three with craniopharyngioma, but not for those with ependymoma. Two of the patients with rhabdoid tumors are alive 16 and 35 months after this diagnosis. There have been no procedure related deaths or complications. CONCLUSION: Cyberknife radiosurgery can be used to achieve local control for some children with CNS tumors without the need for rigid head fixation.

Arsenic trioxide as effective therapy for relapsed acute promyelocytic leukemia.

The standard of treatment for newly diagnosed patients with acute promyelocytic leukemia (APL) is all-trans retinoic acid (ATRA) plus anthracycline-based cytotoxic chemotherapy, a combination that is highly effective for remission induction. However, 20%-30% of patients relapse and require salvage therapy. Reports from China on the striking efficacy and safety of arsenic trioxide in patients with APL led to clinical trials in the United States, which culminated in U.S. Food and Drug Administration approval in September 2000. Trisenox (Cell Therapeutics, Inc., Seattle, WA) is an injectable formulation of arsenic trioxide indicated in the treatment of refractory or relapsed APL. The common side effects of Trisenox therapy are mostly mild and self-limiting and do not require interruption of therapy. Serious adverse effects that can occur include hyperleukocytosis, electrocardiographic abnormalities, and APL differentiation syndrome. These effects can be prevented or managed successfully with careful patient monitoring during treatment. Trisenox has no known cross-resistance with ATRA or other anticancer agents. It does not cause hair loss and is not myelosuppressive in patients with APL. Oncology nurses can play a major role in educating patients about this new drug, explaining its clinical benefits and side effects and the precautions that are necessary for its use.