Mechanisms of resistance to systemic therapy in metastatic castration-resistant prostate cancer

Publication date: Available online 8 May 2017
Source:Cancer Treatment Reviews
Author(s): Giuseppe Galletti, Benjamin I. Leach, Linda Lam, Scott T. Tagawa
Patients with metastatic castration-resistant prostate cancer (mCPRC) now have an unprecedented number of approved treatment options, including chemotherapies (docetaxel, cabazitaxel), androgen receptor (AR)-targeted therapies (enzalutamide, abiraterone), a radioisotope (radium-223) and a cancer vaccine (sipuleucel-T). However, the optimal treatment sequencing pathway is unknown, and this problem is exacerbated by the issues of primary and acquired resistance. This review focuses on mechanisms of resistance to AR-targeted therapies and taxane-based chemotherapy.Patients treated with abiraterone, enzalutamide, docetaxel or cabazitaxel may present with primary resistance, or eventually acquire resistance when on treatment. Multiple resistance mechanisms to AR-targeted agents have been proposed, including: intratumoral androgen production, amplification, mutation, or expression of AR splice variants, increased steroidogenesis, upregulation of signals downstream of the AR, and development of androgen-independent tumor cells. Known mechanisms of resistance to chemotherapy are distinct, and include: tubulin alterations, increased expression of multidrug resistance genes, TMPRSS2-ERG fusion genes, kinesins, cytokines, and components of other signaling pathways, and epithelial-mesenchymal transition. Utilizing this information, biomarkers of resistance/response have the potential to direct treatment decisions. Expression of the AR splice variant AR-V7 may predict resistance to AR-targeted agents, but available biomarker assays are yet to be prospectively validated in the clinic.Ongoing prospective trials are evaluating the sequential use of different drugs, or combination regimens, and the results of these studies, combined with a deeper understanding of mechanisms of primary and acquired resistance to treatment, have the potential to drive future treatment decisions in mCRPC.



http://ift.tt/2puFusQ

A Twenty-Four-Year-Old Woman with Left Flank Lipoma-Like Hibernoma

A 24-year-old woman presented with a 5-month history of a left flank mass that was painful on palpation. Magnetic resonance imaging revealed a 10.0 × 6.0 × 2.5 cm mass consistent with lipoma. A fatty lobulated mass was excised and subjected to H#38;E staining and immunohistochemical analyses. The specimen consisted of mature univacuolated adipocytic cells, with intermixed multivacuolated eosinophilic granular cells. No atypia or hyperchromasia was identified. Most of the cells were S100 positive and Ki-67 immunonegative. A diagnosis of a lipoma-like hibernoma was rendered. Hibernomas are rare benign lipomatous tumors that show differentiation toward brown fat. The lipoma-like hibernoma subtype is rare and can be misdiagnosed as atypical lipoma or well-differentiated liposarcoma. Here we describe an example of this rare tumor.
Case Rep Oncol 2017;10:438–441

http://ift.tt/2qMueMx

Effect of the Combination of Trabectedin and Pegylated Liposomal Doxorubicin in a BRCA2 Mutation Carrier with Recurrent Platinum-Sensitive Ovarian Cancer

Introduction: The current standard of care for ovarian cancer is optimal cytoreduction with adjuvant chemotherapy based on a platinum/taxane combination. Although the response rate to this therapy is high, most patients ultimately relapse. Response to second-line therapy and prognosis are linked to the platinum-free interval (PFI); when both improve, the PFI increases. As a result, there is an increasing interest in the PFI extension strategies including platinum-free combinations. Case Presentation: A 50-year-old postmenopausal woman presented with ovarian serous carcinoma with peritoneal carcinomatosis. First-line neoadjuvant chemotherapy with carboplatin plus paclitaxel was initiated, followed by surgery and carboplatin plus paclitaxel chemotherapy. Eight months after the last cycle, CT revealed extensive supra- and infradiaphragmatic node involvement, and second-line chemotherapy was initiated with trabectedin and pegylated liposomal doxorubicin (PLD). Partial response was achieved and successfully maintained for 18 cycles. After the 18th cycle and a 25-month PFI, CT imaging evidenced disease progression. As the patient was a BRCA2 mutation carrier, third-line chemotherapy was initiated with carboplatin and gemcitabine every 3 weeks. After the third cycle, imaging confirmed complete response, which was maintained after the sixth and final cycle. Maintenance treatment with olaparib was initiated. At present – 6 months after the start of maintenance chemotherapy with olaparib – the patient is disease free. Conclusions: Second-line chemotherapy with a nonplatinum combination – trabectedin plus PLD – was effective in a BRCA2 mutation carrier with recurrent partially platinum-sensitive ovarian cancer.
Case Rep Oncol 2017;10:433–437

http://ift.tt/2pqzIrk

Pneumothorax during Pemetrexed Treatment in a Patient with Non-Small Cell Lung Cancer: A Case Report and Literature Review

Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in non-small cell lung cancer. A 70-year-old male presented with a stage IV non-small cell lung cancer. The patient was treated with pemetrexed as third-line chemotherapy. However, a pneumothorax occurred 16 days after the administration of the second cycle of pemetrexed. The pneumothorax was slight and the patient was observed without undergoing any additional treatment. Twenty-four days after its initial occurrence, the pneumothorax had improved. This is the first case of pneumothorax that has been observed during pemetrexed treatment. Pneumothorax during chemotherapy is rare; however, it is a life-threatening complication and should not be overlooked.
Case Rep Oncol 2017;10:428–432

http://ift.tt/2qMQrtP

Cancers, Vol. 9, Pages 49: Diagnostic and Therapeutic Potential of MicroRNAs in Lung Cancer

Lung cancer is the leading cause of deaths resulting from cancer owing to late diagnosis and limited treatment intervention. MicroRNAs are short, non-coding RNA molecules that regulate gene expression post-transcriptionally by translational repression or target messenger RNA degradation. Accumulating evidence suggests various roles for microRNAs, including development and progression of lung cancers. Because microRNAs are degraded to a much lesser extent in formalin-fixed paraffin-embedded specimens and are present not only in tumor tissues but also in body fluids, there is an increased potential in microRNA analyses for cancer research. In this review, recent studies of microRNA are introduced and briefly summarized, with a focus on the association of microRNAs with histological subtypes, genetic driver alterations, therapeutically-targeted molecules, and carcinogens. The reported circulating microRNA signature for the early detection of lung cancer and the implications of microRNAs as the modulators of tumor immune response are also introduced.

http://ift.tt/2qUOtEb

Renal medullary carcinoma: A national analysis of 159 patients

Abstract

Background

Renal medullary carcinoma (RMC) is an aggressive malignancy seen predominantly in young males with sickle cell trait. RMC is poorly understood, with fewer than 220 cases described in the medical literature to date. We used a large national registry to define the typical presentation, treatments, and outcomes of this rare tumor.

Methods

The National Cancer Database was queried for patients under 40 years of age diagnosed with RMC from 1998 to 2011. An analysis of patient and tumor characteristics, treatment details, and overall survival (OS) was undertaken, and factors associated with mortality were identified using multivariable regression analysis.

Results

In total, 159 patients with RMC were identified, of whom a majority were male (71%), African American (87%), and had metastatic disease (71%). Median tumor size was 6 cm and median survival was 7.7 months. Most patients underwent surgery (60%) and chemotherapy (65%). Few patients received radiation (12%). Patients with metastatic disease had a significantly worse median survival (4.7 vs. 17.8 months, P < 0.001) and were less likely to receive surgery (42% vs. 91%, P < 0.001). Age and tumor size did not appear to impact OS.

Conclusion

In the largest cohort to date of patients with RMC, we found a dismal median survival of less than 8 months. Age and tumor size were not associated with OS. Metastatic disease at presentation was the main negative prognostic indicator in RMC and was present in a majority of patients at the time of diagnosis.

http://ift.tt/2qMaMiT

A novel compound heterozygous form of severe protein C deficiency causing bleeding without purpura fulminans

http://ift.tt/2ppAl4o