Gabrielle B. Rocque

The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation

Richter syndrome (RS) represents the development of diffuse large B-cell lymphoma in the context of chronic lymphocytic leukemia. The scarcity of biologic information about RS has hampered the identification of molecular predictors of RS outcome. We addressed this issue by performing a comprehensive molecular characterization of 86 pathologically proven RS. TP53 disruption (47.1%) and c-MYC abnormalities (26.2%) were the most frequent alterations, whereas common genetic lesions of de novo diffuse large B-cell lymphoma were rare or absent. By multivariate analysis, lack of TP53 disruption (hazard ratio, 0.43; P = .003) translated into significant survival advantage with 57% reduction in risk of death. An algorithm based on TP53 disruption, response to RS treatment, and Eastern Cooperative Oncology Group performance status had 80.9% probability of correctly discriminating RS survival (c-index = .809). RS that were clonally unrelated to the paired chronic lymphocytic leukemia phase were clinically and biologically different from clonally related RS because of significantly longer survival (median, 62.5 months vs 14.2 months; P = .017) and lower prevalence of TP53 disruption (23.1% vs 60.0%; P = .018) and B-cell receptor stereotypy (7.6% vs 50.0%; P = .009). The molecular dissection of RS into biologically distinct categories highlights the genetic heterogeneity of this disorder and provides clinically relevant information for refining the prognostic stratification of patients.

Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles

The chemotherapy drug paclitaxel causes tumor regression and cell death by inducing high rates of chromosome missegregation on multipolar spindles. The Secret Life of Paclitaxel The classic chemotherapy drug paclitaxel is a standard part of treatment for breast cancer and other malignancies. Although it is commonly understood to act as a microtubule poison and lead to mitotic arrest, this knowledge is largely based on studies of cells in culture, with drug concentrations that may not be realistic. Now, Zasadil and coauthors measured the concentration of paclitaxel in real patients undergoing treatment with the drug, and then investigated the response of cancer cells to paclitaxel at these lower and more realistic concentrations. Unexpectedly, the cells treated under these conditions did not undergo mitotic arrest, but instead proceeded through mitosis with abnormal spindles, resulting in chromosome missegregation, which leads to tumor cell death. This intriguing discovery demonstrates that we may not know as much as we thought about the effects of one of our most common chemotherapy drugs. In addition, the findings from this study may lead to clinical applications both in optimizing the selection of chemotherapy drug combinations and in determining which patients are likely to respond to paclitaxel treatment. The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, most mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs because of chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future antimitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel.

MiRNA expression in diffuse large B-cell lymphoma treated with chemoimmunotherapy

Diffuse large B-cell lymphoma (DLBCL) prognostication requires additional biologic markers. miRNAs may constitute markers for cancer diagnosis, outcome, or therapy response. In the present study, we analyzed the miRNA expression profile in a retrospective multicenter series of 258 DLBCL patients uniformly treated with chemoimmunotherapy. Findings were correlated with overall survival (OS) and progression-free survival (PFS). miRNA and gene-expression profiles were studied using microarrays in an initial set of 36 cases. A selection of miRNAs associated with either DLBCL molecular subtypes (GCB/ABC) or clinical outcome were studied by multiplex RT-PCR in a test group of 240 cases with available formalin-fixed, paraffin-embedded (FFPE) diagnostic samples. The samples were divided into a training set (123 patients) and used to derive miRNA-based and combined (with IPI score) Cox regression models in an independent validation series (117 patients). Our model based on miRNA expression predicts OS and PFS and improves upon the predictions based on clinical variables. Combined models with IPI score identified a high-risk group of patients with a 2-year OS and a PFS probability of < 50%. In summary, a precise miRNA signature is associated with poor clinical outcome in chemoimmunotherapy-treated DLBCL patients. This information improves upon IPI-based predictions and identifies a subgroup of candidate patients for alternative therapeutic regimens.

Inpatient Hospitalization of Oncology Patients: Are We Missing an Opportunity for End-of-Life Care?

INTRODUCTIONnDespite advances in the care of patients with cancer over the last 10 years, cancer remains the second leading cause of death in the United States. Many patients receive aggressive, in-hospital end-of-life care at high cost. There are few data on outcomes after unplanned hospitalization of patients with metastatic cancer.nnnMETHODSnIn 2000 and 2010, data were collected on admissions, interventions, and survival for patients admitted to an academic inpatient medical oncology service.nnnRESULTSnThe 2000 survey included 191 admissions of 151 unique patients. The 2010 survey assessed 149 admissions of 119 patients. Lung, GI, and breast cancers were the most common cancer diagnoses. In the 2010 assessment, pain was the most common chief complaint, accounting for 28%. Although symptoms were the dominant reason for admission in 2010, procedures and imaging were common in both surveys. The median survival of patients after discharge was 4.7 months in 2000 and 3.4 months in 2010. Despite poor survival in this patient population, hospice was recommended in only 23% and 24% of patients in 2000 and 2010, respectively. Seventy percent of patients were discharged home without additional services.nnnCONCLUSIONnOn the basis of our data, an unscheduled hospitalization for a patient with advanced cancer strongly predicts a median survival of fewer than 6 months. We believe that hospital admission represents an opportunity to commence and/or consolidate appropriate palliative care services and end-of-life care.

Palliative care reduces morbidity and mortality in cancer.

Despite improvements in cancer therapies, cancer is the leading cause of death worldwide. Many patients experience severe, unnecessary symptoms during treatment as well as at the end of life. Often, patients receive aggressive care at the end of life that is discordant with their preferences. Palliative care is an approach that focuses on communication and quality of life, including treatment of physical, psychosocial, and spiritual suffering. This approach is appropriate for patients with life-limiting cancer, throughout the course of their disease. A growing body of evidence supports the integration of palliative care into routine cancer care, owing to the benefits in symptom control, quality of life, patient satisfaction, and resource utilization. Palliative care can be delivered in inpatient, outpatient, and home-based settings. The specialty and associated infrastructure is expanding rapidly with support from the international medical community. The ideal model of how to incorporate palliative care providers into the care of patients with cancer is yet to be defined; future research is needed to develop delivery systems and improve access to palliative care services. Through collaboration between oncologists and palliative care teams, there is hope of improving the quality of care for patients with both curable and life-limiting cancers.

Adjuvant Therapy for HER2+ Breast Cancer: Practice, Perception and Toxicity

Multiple adjuvant regimens are used for HER2+ breast cancer, but experience in routine practice is not reported. We evaluated whether oncologists’ perceptions of these regimens matches clinical experience. We surveyed Wisconsin medical oncologists throughout the state regarding factors impacting selection of TCH (docetaxel, carboplatin, and trastuzumab) or anthracycline-based therapy. We also reviewed 200 cases of HER2+ breast cancer treated at the University of Wisconsin and the Marshfield Clinic and collected data on patient and tumor characteristics, chemotherapy regimen, and toxicities. Two-thirds of surveyed oncologists prefer anthracycline-based therapy, particularly for node-positive cancers. However, TCH was preferred for early-stage (T1a-bN0) tumors. Half of oncologists use prophylactic G-CSF with TCH. In the 200 cases reviewed at our centers, acute toxicity occurred more frequently with TCH. There were fewer dose modifications or delays for AC-TH (doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab) than TCH (31% vs. 47%, Pxa0=xa00.07), possibly due to higher use of prophylactic G-CSF with AC-TH (77% vs. 34% with TCH, Pxa0<xa00.001). Fifteen patients received prophylactic G-CSF during TCH; none developed neutropenic fever. In contrast, 25% developed neutropenic fever during TCH without G-CSF. There were modest declines in median left ventricular ejection fraction reaching 9% with AC-TH and 3% with TCH at 12xa0months, but early cessation of trastuzumab was similar for both regimens. We conclude that TCH and AC-TH are common adjuvant regimens used for HER2+ breast cancer. The preference of TCH for early-stage disease and anthracycline-based therapy for node-positive disease suggests that many oncologists perceive that TCH is safer and AC-TH more effective. Myelosuppression from TCH is greater than AC-TH, but can be mitigated with routine G-CSF.

Update on Adjuvant Chemotherapy for Early Breast Cancer

Breast cancer is the second most common cancer in women worldwide. Although most women are diagnosed with early breast cancer, a substantial number recur due to persistent micro-metastatic disease. Systemic adjuvant chemotherapy improves outcomes and has advanced from first-generation regimens to modern dose-dense combinations. Although chemotherapy is the cornerstone of adjuvant therapy, new biomarkers are identifying patients who can forego such treatment. Neo-adjuvant therapy is a promising platform for drug development, but investigators should recognize the limitations of surrogate endpoints and clinical trials. Previous decades have focused on discovering, developing, and intensifying adjuvant chemotherapy. Future efforts should focus on customizing therapy and reducing chemotherapy for patients unlikely to benefit. In some cases, it may be possible to replace chemotherapy with treatments directed at specific genetic or molecular breast cancer subtypes. Yet, we anticipate that chemotherapy will remain a critical component of adjuvant therapy for years to come.

Development and evaluation of a survey to assess survivor knowledge change after survivorship care plans: WiSDOM-B (Wisconsin Survey of cancer DiagnOsis and Management in Breast cancer).

The oncology community has increased efforts to inform survivors about long-term risks and planned follow-up after cancer treatment. Survivorship care plans (SCPs) have been recommended since 2005, yet the benefits of implementation are only now being emphasized. SCPs are hypothesized to enhance patient knowledge. The Wisconsin Survey of Diagnosis and Management in Breast Cancer (WiSDOM-B) was developed to measure changes in breast cancer survivor knowledge pre- and postdelivery of an SCP. The WiSDOM-B was developed with input from oncologists (medical, radiation, and surgical), patient advocates, cancer survivors, and survey design experts. Initially, nine patients evaluated survey content, and modifications were made to enhance clarity. Subsequently, 38 patients were enrolled in a randomized pilot trial assessing SCP impact on knowledge of diagnosis, treatment, late effects, and follow-up (WiSDOM-B) and satisfaction with knowledge (existing survey). The WiSDOM-B was developed using feedback from multiple stakeholders. Baseline knowledge was poor and remained stable in the control arm. There was a suggestion of increased survivor knowledge following receipt of SCPs in the intervention arm (68.4 vs. 74.4xa0%). Change was not statistically significant compared with the control arm. Despite knowledge deficits, baseline satisfaction with knowledge was high for both groups, with 100xa0% of patients being satisfied/very satisfied with information provided. Satisfaction did not change significantly following SCP receipt. The WiSDOM-B assesses survivor knowledge of cancer diagnosis, treatment, follow-up, and side effects. It will be a useful tool for future studies assessing the impact of care plans on survivor knowledge.

Choosing Wisely in Oncology: Are We Ready For Value-Based Care?

INTRODUCTIONnIn 2012, ASCO created the Top Five Choosing Wisely (CW) list of low-value tests and procedures for which there is little evidence of benefit. ASCOs Quality Oncology Practice Initiative, an oncologist-led practice-based quality assessment program, includes measures on the basis of these recommendations.nnnMETHODSnCW test measures from spring and fall 2013, spring 2014, and spring 2015 were evaluated for concordance rates, change in the concordance over time, and variability by practice characteristics. Practice characteristics recorded included geographic location, academic affiliation, number of new cases, number of medical oncologists, and rounds of participation in Quality Oncology Practice Initiative. Medians, interquartile ranges, and percentages were calculated for concordance with recommendations and practice characteristics. Change in recommendation concordance over time was assessed using linear regression models.nnnRESULTSnFrom 2013 to 2015, 341 unique oncology practices abstracted the CW measures. Performance varied for specific recommendations. The median concordance was best for measure 1 (patients with low or undocumented performance status who received chemotherapy), where concordance ranged from 78.4% to 83.3%. The lowest concordance was for measure 3 (use of biomarkers or advanced imaging tests for surveillance in early breast cancer), where concordance ranged from 67.7% to 74.2%. Performance on CW measures varied markedly by individual practice. Variability over time and by practice characteristics was observed.nnnCONCLUSIONnPerformance on ASCOs CW demonstrates room for improvement. Concordance rates varied substantially by practice. Further education on CW measures is needed to improve patient care and enhance value.

An Unusual Presentation of Liver Failure in a Patient with Primary Gastrointestinal Hodgkin's Lymphoma

Introduction. Hodgkins lymphoma (HL) presenting either with primary bowel involvement or with cholestasis is unusual. The combination of primary gastrointestinal HL presenting with cholestasis and ductopenia has not been previously described. Case Report. We present a case of primary gastrointestinal HL with evidence of liver involvement, but also with prominent ductopenia on liver biopsy and associated intrahepatic cholestasis. A 50-year-old man with a history of Crohns disease presented with a bowel obstruction, for which he underwent a small bowel resection. Histology revealed HL. His course was complicated by cholestatic liver failure. A subsequent liver biopsy revealed both focal involvement by lymphoma and ductopenia, resembling vanishing bile duct syndrome (VBDS). He was treated with chemotherapy with improvement in his cholestasis, but he eventually succumbed due to further complications of his disease and treatment toxicities. Conclusion. This case of primary gastrointestinal HL associated with ductopenia does not meet classic criteria for VBDS, but the clinical presentation and pathology are suggestive of a VBDS-like paraneoplastic process. Therapies for HL in the setting of cholestatic liver failure require special consideration, but some reports of durable remissions and recovery of liver function have been reported.