Efficacy of tyrosine kinase inhibitors in patients with non-small-cell lung cancer with performance status 4: a case series and review of the literature.

BACKGROUND: Current guidelines for non-small-cell lung cancer (NSCLC) recommend that each tyrosine kinase inhibitor (TKI) is indicated even for driver mutation-positive patients with a poor performance status (PS). In previous studies, most patients had a PS of 2-3, but those with a PS of 4 were very few. Therefore, the efficacy of TKIs in patients with NSCLC with a PS of 4 remains unclear. CASE PRESENTATION: We retrospectively reviewed the clinical records of four patients with NSCLC with PS 4 treated with TKIs: an 89-year-old Japanese woman (Case 1), a 80-year-old Japanese woman (Case 2), an 50-year-old Japanese man (Case 3), and a 81-year-old Japanese woman (Case 4). Genetic alterations were epidermal growth factor receptor (EGFR), MET exon 14 skipping, BRAFV600E, and ROS1 proto-oncogene receptor tyrosine kinase (ROS1). One case with ROS1 fusion showed a significant response with the recovery of PS. However, in the remaining three cases (i.e., EGFR, MET exon 14 skipping, and BRAFV600E mutations), patients died despite the administration of TKIs. These three patients had to be hospitalized at the end of their life to receive treatment. CONCLUSIONS: This is the first case series to summarize the efficacy of TKIs in patients with NSCLC with a PS of 4. Additionally, this case series poses a question concerning the indication of TKIs for older patients with a PS of 4.

Dabrafenib plus trametinib treatment for a patient with BRAF V600E-mutated large-cell lung carcinoma and a poor performance status.

Dabrafenib plus trametinib is active against metastatic lung cancer with the BRAF V600E mutation. However, the feasibility of dabrafenib plus trametinib for patients with a poor performance status (PS) has not been reported. We report the case of an 80-year-old woman was diagnosed with metastatic large-cell lung carcinoma. Her general statuses worsened due to cancer, resulting in a PS of 4. Genotype testing revealed a BRAF V600E mutation. The patient received dabrafenib plus trametinib without significant adverse effects. This report is the first to describe dabrafenib plus trametinib administration for large-cell lung carcinoma in a patient with a poor PS.

Acute Lower Extremity Arterial Thrombosis Associated with Osimertinib-Induced Erythrocytosis.

BACKGROUND Osimertinib is an oral third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) approved as first-line therapy for advanced non-small cell lung cancer (NSCLC) with positive EGFR mutation. Rashes, nail toxicity, and diarrhea are common adverse events. Hematological adverse effects, including anemia, thrombocytopenia, and lymphocytopenia, have been reported. However, erythrocytosis has not been reported as an adverse event. To the best of our knowledge, we report the first case of acute lower extremity thrombosis presumably caused by osimertinib-induced erythrocytosis. CASE REPORT A 70-year-old man with epidermal EGFR-mutant advanced NSCLC presented with acute left sural pain. The patient's left foot was cold, and peripheral arterial Doppler signals were absent. He had developed erythrocytosis of unknown etiology during osimertinib therapy. Hemoglobin (Hb) and hematocrit were 22.6 g/dL and 62.5%, respectively. Contrast-enhanced computed tomography showed thrombotic occlusion of the popliteal artery. Other than erythrocytosis, there was no possible cause of arterial thrombosis. Osimertinib was discontinued immediately because the NSCLC started to resist treatment and was presumed to be the cause of erythrocytosis. He received endovascular treatment (EVT). Following serial EVT and debridement, his fourth toe was amputated for necrosis. Erythrocytosis persisted 8 months during osimertinib therapy. Hb levels decreased to 15.4 mg/dL due to blood loss complicated with catheter thrombectomy and remained normal for 20 months after osimertinib discontinuation. The patient died of cancer progression. CONCLUSIONS This case suggests the erythrocytosis was possibly caused by osimertinib. We may need to monitor Hb levels during osimertinib therapy and be alert to thrombosis once Hb starts to rise.

Lower response to trastuzumab emtansine in metastatic breast cancer patients with human epidermal growth factor receptor 2 immunohistochemistry score of 2 and fluorescence in situ hybridization positive compared with immunohistochemistry score of 3: a retrospective study.

Tumor human epidermal growth factor receptor 2 (HER2) status is defined by either protein expression using immunohistochemistry (IHC) or gene amplification using fluorescence in situ hybridization (FISH). Approximately 20% of HER2-positive breast cancer is HER2 IHC 2+/FISH-positive. Unlike trastuzumab, it has not been studied whether the response to trastuzumab emtansine (T-DM1) differs according to HER2-positive status. We retrospectively identified and reviewed medical records of all patients with HER2-positive advanced breast cancer (ABC) who received T-DM1 in our hospital from October 2013 to December 2016. We compared the objective response rate (ORR) and progression-free survival (PFS) between patients in the HER2 IHC 3+ group and those in the HER2 IHC 2+/FISH-positive group. A total of 39 patients (IHC 3+: n = 32; IHC 2+/FISH-positive: n = 7) were analyzed. Nineteen (48.7%), 13 (33.3%), and 29 (74.4%) patients had received at least one prior chemotherapy, more than three lines of chemotherapy, and prior pertuzumab for ABC, respectively. ORR was significantly higher in the IHC 3+ group than in the IHC 2+/FISH-positive group (53.3% vs. 0%, P = 0.024). Median PFS was 7.9 months in the IHC 3+ group versus 3.9 months in the IHC 2+/FISH-positive group (hazard ratio 0.68; 95% confidence interval 0.28-1.69, P = 0.408). Among the HER2-positive ABC patients treated with T-DM1, ORR was significantly worse in HER2 IHC 2+/FISH-positive than in HER2 IHC 3+ patients. Median PFS tended to be shorter in patients with HER2 IHC 2+/FISH-positive.

Pilot Phase II Trial of Bevacizumab Monotherapy in Nonmetastatic Castrate-Resistant Prostate Cancer.

Introduction/Background. Nonmetastatic castrate resistant prostate cancer (CRPC) is a challenging disease state. The objective of this study was to evaluate the efficacy and tolerability of bevacizumab in nonmetastatic CRPC patients. Patients. Patients with prostate cancer who developed PSA recurrence after local therapy were included if they had absence of bone or visceral metastases and PSA progression despite androgen deprivation therapy. Methods. Bevacizumab 10 mg/kg intravenously was administered every 14 days until PSA progression, development of metastasis, or unacceptable toxicity. Results. 15 patients were enrolled and treated with bevacizumab for a median duration of 3.1 months. Median baseline PSA was 27 ng/mL, and seven patients had Gleason Score ≥8. Five patients had declined in PSA during the treatment. Median PSA doubling time was prolonged from 4.7 months pretreatment to 6.5 months. Median time to PSA progression and new metastasis were 2.8 and 7.9 months, respectively. There were three grade 3 adverse events (one proteinuria and two hypertension) and one pulmonary embolism. There was no treatment-related mortality. Conclusion. Bevacizumab therapy had minimal impact on the disease course of nonmetastatic CRPC, and investigation of novel strategies is needed.

Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs.

The activation of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway is a known causal mechanism of oncogenesis and resistance to cancer treatments. The process of PI3K-Akt pathway activation is complex and includes receptor tyrosine kinase(RTK) activation, PIK3CA mutations, loss of phosphatase and tensin homolog (PTEN), Akt mutations, tuberous sclerosis complex (TSC) mutations, and Ras homologue enriched in brain (RHEB) gene amplifications. The blockage of mammalian target of rapamycin (mTOR), the key downstream pathway protein, has been successful in selected cancer types, with mTOR-targeting agents available for clinical use. Other novel drugs blocking this pathway such as PI3K inhibitors, Akt inhibitors and PDK-1 inhibitors are currently only available for investigational use, but have shown promise as cancer therapies in both preclinical and early phase clinical studies. The newer generations of these inhibitors are more specific and have improved potency and safety. The combinations of targeted treatments against this pathway, blocking multiple different steps, are under preliminary investigation. Further research is needed to identify the biomarkers that predict treatment response and resistance in order to optimize personalized medicine.

Refining the treatment of advanced nonsmall cell lung cancer.

Metastatic nonsmall cell lung cancer (NSCLC) is a debilitating and deadly disease with virtually no chance for long-term survival. Chemotherapy has improved both survival and quality of life for patients with advanced disease. Overall survival of patients with metastatic NSCLC has gradually increased from 8 to 12 months over the past three decades with the introduction of new chemotherapeutic drugs and agents directed at novel targets in the cancer cell. Epidermal growth factor receptor and vascular endothelial growth factor are two such targets. Recent developments also include treatment based on histology and the use of maintenance therapy. It has been recognized that lung cancer is a very complex disease. It is common practice to include a number of scientific correlative studies in the design of clinical trials in order to determine predictive markers of benefit from treatment. This article will review the current approach to the treatment of advanced NSCLC including the use of chemotherapy and molecularly targeted agents. Future directions including the use of potentially predictive biomarkers and innovative clinical trials aimed at a more individualized approach to treatment will also be discussed.

Paraneoplastic cerebellar degeneration with anti-Yo antibody in a patient with HER2/neu overexpressing breast cancer: a case report with a current literature review.

Paraneoplastic cerebellar degeneration (PCD) is a rare paraneoplastic syndrome, occurring in <1% of breast cancers. We describe a 32-year-old female presenting with ataxia subsequently diagnosed with poorly differentiated breast cancer. She was serum anti-Yo antibody positive, with estrogen/progesterone receptor negative and HER2/neu receptor positive breast cancer. Neurological symptoms progressed despite modified radical mastectomy, supraclavicular lymphadenectomy, intravenous immunoglobulin, corticosteroids, transtuzumab, and combination chemotherapy. We performed a literature search, which found a possible association between anti-Yo positive PCD and HER2/neu-expressing breast cancer.

Endoscopic ultrasound fine-needle aspiration in the staging of non-small-cell lung cancer.

Precise mediastinal staging of non-small-cell lung cancer is extremely important, as mediastinal lymph node metastases generally indicate unresectable disease. Reliance on computed tomography (CT) and positron-emission tomography (PET) alone to stage and determine resectability is limited by false-positive results. Whenever possible, pathologic confirmation of metastases is desirable. Mediastinoscopy and transbronchial fine-needle aspiration are widely established but imperfect modalities. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) has emerged as a diagnostic and staging tool because of its safety, accuracy, and patient convenience. We reviewed 13 prospective studies evaluating the comparative performance of EUS for staging lung cancer. We conclude that EUS is a valuable staging modality. Further studies of the role of EUS compared to other modalities such as integrated PET/CT and endobronchial ultrasound (EBUS) are forthcoming.