Jason Zhu

Temporal trends in oropharyngeal cancer treatment and survival: 1998-2009.

To describe temporal trends of surgical and nonsurgical treatment for advanced oropharyngeal cancer, and to report contemporary survival estimates and factors associated with survival.

Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond

Immune checkpoint inhibitors targeting the PD-1 pathway have greatly changed clinical management of metastatic urothelial carcinoma and metastatic renal cell carcinoma. However, response rates are low, and biomarkers are needed to predict for treatment response. Immunohistochemical quantification of PD-L1 was developed as a promising biomarker in early clinical trials, but many shortcomings of the four different assays (different antibodies, disparate cellular populations, and different thresholds of positivity) have limited its clinical utility. Further limitations include the use of archival specimens to measure this dynamic biomarker. Indeed, until PD-L1 testing is standardized and can consistently predict treatment outcome, the currently available PD-L1 assays are not clinically useful in urothelial and renal cell carcinoma. Other more promising biomarkers include tumor mutational burden, profiles of tumor infiltrating lymphocytes, molecular subtypes, and PD-L2. Potentially, a composite biomarker may be best but will need prospective testing to validate such a biomarker.

Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer

Introduction: Over the past decade, treatment options for men with metastatic castration-resistant prostate cancer (CRPC) have expanded with the addition of abiraterone acetate (AA), enzalutamide, sipuleucel-T, radium-223, docetaxel and cabazitaxel. The optimal sequencing of therapies in the context of efficacy and known cross-resistance remains uncertain. Areas covered: We review the development of enzalutamide (MDV3100, Xtandi), a novel second-generation androgen receptor (AR), and AA (Zytiga), a selective, irreversible inhibitor of cytochrome P17. In addition to discussing the clinical evidence, we also address evolving evidence of mechanisms of resistance and clinical cross-resistance during sequential therapy with these agents. Expert opinion: AA and enzalutamide have both demonstrated tolerability and clinical benefit for multiple outcomes in patients with CRPC, in both post-chemotherapy and pre-chemotherapy settings. Both agents target the androgen-signaling pathway and have similar efficacy; however, they differ in prednisone use and their toxicity profiles, impacting the decision of upfront therapy. Mechanisms of resistance emerging after treatment include both alterations in AR signaling as well as mechanisms that bypass the AR. Retrospective analyses have demonstrated evidence that sequential treatment with these agents results in limited clinical benefit, supporting mechanisms of cross-resistance. Trials are ongoing to determine optimal timing, sequence and combination of these agents.

Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies

BACKGROUND The therapeutic armamentarium for metastatic renal cell carcinoma has rapidly expanded over the past decade to include a number of anti-angiogenic therapies and more recently, an immunotherapy. Biomarkers in the peripheral circulation are easily accessible, can provide important prognostic value, and have the potential to give important information about disease progression and treatment sensitivity or response. MAIN FINDINGS Herein, we review a variety of circulating markers including circulating protein markers (VEGF-A, inflammatory cytokines, and LDH), circulating nucleic acids (cell free DNA and micro RNAs), and circulating cellular factors (circulating tumor cells, circulating endothelial cells, and immune cell subsets). We discuss these biomarkers in the context of their ability to provide prognostic and predictive information to anti-angiogenic and immunotherapeutic agents. PRINCIPAL CONCLUSIONS While promising, there is still much work to be done, and prospective evaluation of any potential predictive biomarker for these therapies is greatly needed.

Acute Myeloid Leukemia following Olaparib Treatment in Metastatic Castration Resistant Prostate Cancer

Prostate cancer is the third most common cause of cancer-related deaths among men in the United States. Twenty-five percent to 30% of sporadic castration-resistant prostate cancers are characterized by defects in DNA repair. Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit defects in DNA repair to induce tumor-selective cytotoxicity and are in clinical development for treatment of prostate cancer. Serious adverse events might occur after the use of a PARP inhibitor for patients with metastatic castrationresistant prostate cancer. Long-term safety monitoring will be a necessary end point in evaluating the clinical benefit of PARP inhibitors in patients with genetically susceptible tumors.

A role for the androgen receptor in the treatment of male breast cancer

Male breast cancer (BC) is relatively rare, making up less than 1% of all breast cancer cases in the United States. Treatment guidelines for male BC are derived from studies on the treatment of female BC, and are based molecular and clinical characteristics, such as hormone receptor positivity. For female estrogen receptor positive (ER+) breast cancers, the standard of care includes three classes of endocrine therapies: selective estrogen receptor modulators, aromatase inhibitors, and pure anti-estrogens. In contrast to female ER+ breast cancers, there is less known about the optimal treatment for male ER+ BC. Furthermore, in contrast to ER, less is known about the role of the androgen receptor (AR) in male and female BC. We report here the treatment of a 28-year-old man with metastatic AR+, ER+ breast cancer otherwise refractory to chemotherapy, who has had a durable clinical response to hormonal suppression with the combination of aromatase inhibition (Letrozole) in conjunction with a GnRH agonist (Leuprolide).

Treatment of High-Grade Metastatic Pancreatic Neuroendocrine Carcinoma with FOLFIRINOX.

Standard first-line treatment for poorly differentiated or highgrade neuroendocrine carcinoma (NECA) consists of combination chemotherapy with a platinum agent (either cisplatin or carboplatin) and a topoisomerase inhibitor (etoposide) [1]. This recommendation is derived from large trials in patients with small cell lung cancer, an aggressive variant of NECA, and from several small, non-randomized trials in patients with extrapulmonary NECAs [2, 3]. Recently, the combination of 5fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) was shown to significantly improve response rates and overall survival among patients withmetastatic adenocarcinoma of the pancreas [4].We recently treated two patients with pancreatic NECA using FOLFIRINOX in the first line and in the salvage setting.

Predictors of survival in 211 patients with stage IV pulmonary and gastroenteropancreatic mIBG positive neuroendocrine tumors treated with I-131 mIBG

This retrospective analysis identifies predictors of survival in a cohort of patients with meta-iodobenzylguanidine (MIBG)–positive stage IV pulmonary and gastroenteropancreatic neuroendocrine tumor (P/GEP-NET) treated with 131I-MIBG therapy, to inform treatment selection and posttreatment monitoring. Methods: Survival, symptoms, imaging, and biochemical response were extracted via chart review from 211 P/GEP-NET patients treated with 131I-MIBG between 1991 and 2014. For patients with CT follow-up (n = 125), imaging response was assessed by RECIST 1.1 if images were available (n = 76) or by chart review of the radiology report if images could not be reviewed (n = 49). Kaplan–Meier analysis and Cox multivariate regression estimated survival and progression-free survival benefits predicted by initial imaging, biochemical response, and symptomatic response. Results: All patients had stage IV disease at the time of treatment. Median survival was 29 mo from the time of treatment. Symptomatic response was seen in 71% of patients, with the median duration of symptomatic relief being 12 mo. Symptomatic response at the first follow-up predicted a survival benefit of 30 mo (P < 0.001). Biochemical response at the first clinical follow-up was seen in 34% of patients, with stability of laboratory values in 48%; response/stability versus progression extended survival by 40 mo (P < 0.03). Imaging response (20% of patients) or stability (60%) at the initial 3-mo follow-up imaging extended survival by 32 mo (P < 0.001). Additionally, multiple 131I-MIBG treatments were associated with 24 mo of additional survival (P < 0.05). Conclusion: Therapeutic 131I-MIBG for metastatic P/GEP-NETs appears to be an effective means of symptom palliation. Imaging, biochemical, and symptomatic follow-up help prognosticate expected survival after 131I-MIBG therapy. Multiple rounds of 131I-MIBG are associated with prolonged survival.