Meghan Sri Karuturi

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct subtype of Hodgkin lymphoma that is characterized by unique clinical presentation, histological appearance, and indolent disease course. The recurrent nature of disease provides an opportunity to examine the role of stem cell transplantation in its management. We report here a single-center experience of 26 patients with relapsed NLPHL treated with high-dose chemotherapy and autologous stem cell transplantation between 1990 and 2008. With a median follow-up of 50 months (range, 2-138 months), the 5-year overall and event-free survival were 76% (SE 10%) and 69% (SE 10%), respectively. Our data suggest that high-dose chemotherapy and autologous transplantation should be considered as an option for patients with relapsed NLPHL.

CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers

Deregulation of the cell cycle machinery is a hallmark of cancer. While CDK4/6 inhibitors are FDA approved (palbociclib) for treating advanced estrogen receptor-positive breast cancer, two major clinical challenges remain: (i) adverse events leading to therapy discontinuation and (ii) lack of reliable biomarkers. Here we report that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumours in vivo. Furthermore, intact G1/S transition (Rb-positive and low-molecular-weight isoform of cyclin E (cytoplasmic)-negative) is a reliable prognostic biomarker in ER positive breast cancer patients, and predictive of preclinical sensitivity to this drug combination. Inhibition of CDK4/6 and autophagy is also synergistic in other solid cancers with an intact G1/S checkpoint, providing a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumours.

Chemotherapy-related cognitive impairment in older patients with cancer

Chemotherapy-related cognitive impairment (CRCI) can occur during or after chemotherapy and represents a concern for many patients with cancer. Among older patients with cancer, in whom there is little clinical trial evidence examining side effects like CRCI, many unanswered questions remain regarding risk for and resulting adverse outcomes from CRCI. Given the rising incidence of cancer with age, CRCI is of particular concern for older patients with cancer who receive treatment. Therefore, research related to CRCI in older patients with cancers is a high priority. In this manuscript, we discuss current gaps in research highlighting the lack of clinical studies of CRCI in older adults, the complex mechanisms of CRCI, and the challenges in measuring cognitive impairment in older patients with cancer. Although we focus on CRCI, we also discuss cognitive impairment related to cancer itself and other treatment modalities. We highlight several research priorities to improve the study of CRCI in older patients with cancer.

Approach and Management of Breast Cancer in the Elderly.

Breast cancer is the mostly commonly diagnosed cancer in women both in the United States and worldwide. Although advanced age at diagnosis is associated with more favorable tumor biology, mortality rates are comparatively higher in older adults, possibly attributed to advanced stage at presentation. There are minimal specific treatment-based guidelines in elderly patients with cancer, mostly attributable to their limited inclusion on clinical trials. In addition to the existing evidence from clinical trials and retrospective studies, practitioners need to take into consideration functional status, social support, patient preference, presence of comorbidities, and life expectancy when selecting optimal treatment.

Androgen Receptor Function and Androgen Receptor–Targeted Therapies in Breast Cancer: A Review

Importance The androgen receptor (AR) pathway is emerging as a potential therapeutic target in breast cancer. To date, AR-targeted drugs have been approved only for treatment of prostate cancer; however, AR-targeted treatment for breast cancer is an area of active investigation. Through review of preclinical studies, retrospective clinical studies, and clinical trials, we examined the biology of AR and AR-related pathways, the potential for AR-targeted therapies in breast cancer, and potential biomarkers for AR-targeted treatments. Observations The rate of AR positivity in breast cancer is about 60% to 80%. Biologically, the AR pathway has cross-talk with several other key signaling pathways, including the PI3K/Akt/mTOR and MAPK pathways, and with other receptors, including estrogen receptor and human epidermal growth factor receptor-2. The value of AR positivity as a prognostic marker has not yet been defined. Androgen receptor–targeted therapies, including AR agonists, AR antagonists, and PI3K inhibitors, have shown promising results in clinical trials in patients with breast cancer, and combinations of AR-targeted therapies with other agents have been investigated for overcoming resistance to AR-targeted therapies. Biomarkers to stratify patients according to the likelihood of response to AR-targeted drugs are yet to be established. Potential biomarkers of response to AR inhibitors include AR phosphorylation and AR gene expression. Conclusions and Relevance Androgen receptor–targeted treatments for breast cancer are in development and have shown promising preliminary results. In-depth understanding of AR and AR-related signaling pathways would improve the treatment strategies for AR-positive breast cancer. Further preclinical and clinical studies of AR-targeted drugs alone and in combination with other drugs are justified and warranted to clarify the biology of AR and inform the development of AR-targeted therapies to improve survival outcome in patients with breast cancer.

Understanding cognition in older patients with cancer

Cancer and neurocognitive disorders, such as dementia and delirium, are common and serious diseases in the elderly that are accompanied by high degree of morbidity and mortality. Furthermore, evidence supports the under-diagnosis of both dementia and delirium in older adults. Complex questions exist regarding the interaction of dementia and delirium with cancer, beginning with guidelines on how best measure disease severity, the optimal screening test for either disorder, the appropriate level of intervention in the setting of abnormal findings, and strategies aimed at preventing the development or progression of either process. Ethical concerns emerge in the research setting, pertaining to the detection of cognitive dysfunction in participants, validity of consent, disclosure of abnormal results if screening is pursued, and recommended level of intervention by investigators. Furthermore, understanding the ways in which comorbid cognitive dysfunction and cancer impact both cancer and non-cancer-related outcomes is essential in guiding treatment decisions. In the following article, we will discuss what is presently known of the interactions of pre-existing cognitive impairment and delirium with cancer. We will also discuss identified deficits in our knowledge base, and propose ways in which innovative research may address these gaps.

Has Racial Difference in Cause-Specific Death Improved in Older Patients with Late-Stage Breast Cancer?

BACKGROUND Research on temporal mortality trends for stage IV breast cancer is limited, especially among older patients by race. We evaluated factors associated with overall, breast cancer-specific and other-cause mortalities using contemporary population data. PATIENTS AND METHODS Using the Surveillance, Epidemiology, and End Results-Medicare linked data, we identified older women (≥ 66 years) with stage IV breast cancer diagnosed in 2002-2009. Overall mortality was estimated by the Kaplan-Meier method, compared by log-rank tests, and modeled by Cox models. Competing risk analysis was used to evaluate breast cancer-specific and other-cause mortalities. RESULTS The median overall survival time for non-Hispanic blacks improved from 8.6 months in 2002-2003 to 9.9 months in 2007-2009, whereas that for non-Hispanic whites improved from 12.1 to 14.8 months. In the multivariate model, the risk of breast cancer-specific death for patients diagnosed in 2007-2009 was significantly lower (P = 0.02), whereas the risk of other-cause mortality changed little (P = 0.88) compared with those risks for patients diagnosed in 2002-2003. Non-Hispanic blacks had the higher risk of both mortality types compared with non-Hispanic whites; a diagnosis time-race interaction term was not statistically significant for either cause of death. CONCLUSION Breast cancer-specific mortality among older women modestly improved from 2002 to 2009 across all races, but not other-cause mortality. Racial disparity in mortality persisted, but did not widen in this period. Efforts should be devoted to improving other-cause mortality for all women, with special attention toward decreasing breast cancer mortality for non-Hispanic black women.

Rapid breast cancer disease progression following Cyclin Dependent Kinase 4 and 6 inhibitor discontinuation

Background: CDK 4 and 6 inhibitors (CDK4/6i), which arrest unregulated cancer cell proliferation, show clinical efficacy in breast cancer. Unexpectedly, a patient treated on a CDK4/6i-based trial, as first-line therapy in metastatic breast cancer, developed rapid disease progression following discontinuation of study drug while receiving standard second-line therapy off trial. We thus sought to expand this observation within a population of patients treated similarly at The University of Texas MD Anderson Cancer Center. Methods: Using an IRB-approved protocol, 4 patients previously enrolled on CDK4/6i trials were analyzed for outcomes after discontinuing study drug. These patients were treated on a randomized trial of first-line endocrine therapy +/- a CDK4/6i. Rapid disease progression was defined as progression occurring within 4 months of CDK4/6i discontinuation. Results: In total, 4 patients developed rapid disease progression and died; 2 of whom died within 6 months of CDK4/6i discontinuation. Conclusion: This case series suggests a potential for rapid disease progression following CDK4/6i discontinuation. However, the clinical course following progression must be validated in large CDK4/6i clinical trials and standard-of-care cohorts. If confirmed, such observations may alter the algorithm for subsequent therapy in patients with disease progression on CDK4/6i. Nevertheless, the need remains to define a mechanistic basis for this rapid progression and formulate alternative therapeutic strategies.

Ifosfamide, carboplatin, etoposide with or without bortezomib in patients with relapsed/refractory Hodgkin lymphoma: results of a randomized phase II trial

1 Department of Lyphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2 Department of Lymphoma, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3 Department of Medical Oncology, Thomas Jeff erson Medical College, Philadelphia, PA, USA and Departments of 4 Stem Cell Transplantation and Cellular Therapy, 5 Hematopathology, and 6 Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Targeted agent use in patients with cancer at the end of life.

215 Background: Chemotherapy use at the end of life is considered an indicator of poor quality of care. The use of targeted agent has not been well characterized. In this study, we determined the frequency and predictors of targeted therapy use in the last 30 days of life. METHODS All adult patients residing in the Houston area who died of advanced cancer between September 1, 2009 and February 28, 2010 and had contact with our institution within the last three months of life were included. We collected baseline demographics and data on chemotherapy and targeted agents. RESULTS 816 patients were included: average age 62 (range 21 to 97), female 48% and White 61%. The median interval between the last treatment and death was 47 (interquartile range 21 to 97) days for targeted agents and 57 (26 to 118) days for chemotherapeutic agents. 116 (14%) patients received targeted agents and 147 (18%) received chemotherapy within the last 30 days of life. 43 (5%) patients received targeted agents had concurrent chemotherapy. The most common targeted agents in the last 30 days of life were erlotinib (n=25), bevacizumab (n=20) and rituximab (n=11). In multivariate analysis, younger age, hematologic, and lung malignancies were associated with increased targeted agent use in the last 30 days of life (Table). CONCLUSIONS Targeted agents were used as often as chemotherapy at the end of life, particularly among younger patients and those with hematologic malignancies. Guidelines on targeted therapy use at the end of life are needed. [Table: see text].