Susan E. Bates

Pancreatic Cancer: “A Riddle Wrapped in a Mystery inside an Enigma”

Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult-to-treat cancers. With an increasing incidence and inability to make major progress, it represents the very definition of unmet medical need. Progress has been made in understanding the basic biology—systematic genomic sequencing has led to the recognition that PDAC is not typically a heavily mutated tumor, although there are exceptions. The most consistently mutated genes are KRAS, CDKN2A, TP53, and SMAD4/DPC4. Study of familial PDAC has led to the recognition that a variety of defects in DNA repair genes can be associated with the emergence of pancreatic cancer. Recent studies suggest that epigenetics may play a larger role than previously recognized. A major new understanding is the recognition that PDAC should be considered a composite of tumor cells, as well as pancreatic stellate cells, immune cells, and extracellular matrix. The individual components contribute to metabolic aberration, immune dysfunction, and chemotherapy resistance, and therapeutic innovations may be needed to address them individually. It has also been recognized that metastatic seeding from PDAC occurs very early in the disease course—in an estimated 73% of cases, once the tumor reaches 2 cm. The implication of this is that therapies directed toward micrometastatic disease and increasing fractional cell kill are most needed. Neoadjuvant approaches have been taken to increase resectability and improve outcome. So much work remains, and most critical is the need to understand how this tumor originates and develops. Clin Cancer Res; 23(7); 1629–37. ©2017 AACR. See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”

Current challenges in the management of breast cancer brain metastases

Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287). The utility of human epidermal growth factor 2 (HER2)-directed therapies-lapatinib, ado-trastuzumab emtansine (T-DM1), neratinib and tucatinib-is also being studied in this setting. We address the need for improved imaging techniques and innovation in clinical trial design. For example, the current practice is to initially administer whole-brain radiotherapy (WBRT) as treatment for patients with multiple BCBM. However, in selected circumstances, first-line systemic treatment may be more appropriate in order to avoid neurocognitive toxicities, and potential options should be evaluated in window of opportunity trials. Other strategies that may aid development of more effective clinical trials and expedite the development of promising agents include the use of different clinical endpoints and different imaging tools.

Refining Immunotherapy Approvals

This issue of Clinical Cancer Research includes a CCR Focus on immunotherapy, appearing 10 years after Drs. Zang and Allison in a Focus article introduced our readers to the idea that blocking the PD-L1/PD-1 interaction could enhance antitumor immunity and reverse the poor prognosis conferred by

Romidepsin is effective and well tolerated in older patients with peripheral T-cell lymphoma: analysis of two phase II trials

Abstract Peripheral T-cell lymphomas (PTCLs) are a rare group of lymphoid neoplasms with high relapse rates after initial therapy and poor prognosis. Most patients are aged ≥60 years and are often not candidates for aggressive salvage therapies. Romidepsin, a potent class I histone deacetylase inhibitor, has shown significant single-agent activity in relapsed/refractory PTCL. We evaluated the efficacy and tolerability of romidepsin in elderly patients in this setting. Ninety-five patients aged ≥60 years were identified from 2 prospective phase 2 registration trials of romidepsin, and comparative analyses were performed with younger patients from these trials. Response rates, progression-free survival, and overall survival were not statistically different for younger vs older patients. The toxicity profile in older and younger patients was similar in both trials. Romidepsin demonstrated similar efficacy and tolerability in younger and older patients and presents an attractive treatment option for relapsed/refractory PTCL regardless of age. Trial registration: Clinicaltrials.gov identifiers: NCT00426764, NCT00007345.

Pancreatic Cancer: Challenge and Inspiration

The recent enthusiasm over new discoveries in cancer immunotherapy has made it painfully evident how difficult progress in the therapy of pancreatic cancer has been and how very difficult it remains. If you are lucky (25% of those diagnosed), you are able to undergo curative resection to then

A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat

PurposeBelinostat is a second-generation histone deacetylase inhibitor (HDI) predominantly metabolized by UGT1A1-mediated glucuronidation. Two common polymorphisms (UGT1A1*28 and UGT1A1*60) were previously associated with impaired drug clearance and thrombocytopenia risk, likely from increased drug exposure. This latter phenomenon has been observed with other HDIs such as abexinostat, panobinostat, romidepsin, and vorinostat. It was the intention of this brief report to expand a population pharmacokinetic (PPK) model to include a pharmacodynamic (PD) model describing the change in platelet levels in patients with cancer administered belinostat as a 48-h continuous intravenous infusion, along with cisplatin and etoposide.MethodsThe PPK/PD model developed here introduced an additional rate constant to a commonly used mechanistic myelosuppression model to better describe the maturation of megakaryocytes into platelets before degradation and a feedback mechanism. The model employed a proportional error model to describe the observed circulating platelet data.ResultsSeveral covariates were explored, including sex, body weight, UGT1A1 genotype status, liver, and kidney function, but none significantly improved the model. Platelet levels rebounded to baseline within 21 days, before the next cycle of therapy. Simulations predicted that higher belinostat drug exposure does cause lower thrombocyte nadirs compared to lower belinostat levels. However, platelet levels rebound by the start of the next belinostat cycle.ConclusionsThis model suggests a q3week schedule allows for sufficient platelet recovery before the next belinostat infusion is optimal.

Clinical Trials in Pancreatic Cancer: A Long Slog

Many investigators have turned their efforts toward improving the gemcitabine/nab‐paclitaxel combination by the addition of a third agent. This commentary highlights efforts to date, including the Clinical Trial Results by Ko et al.: A Randomized Double‐Blinded Phase II Trial of Gemcitabine and Nab‐Paclitaxel Plus Apatorsen or Placebo in Patients with Metastati Pancreatic Cancer: The RAINIER Trial.

Multiple Myeloma: Multiplying Therapies

Multiple myeloma must have among the most, if not the most, FDA approvals for any one malignancy. If the four liposomal doxorubicin approvals are counted separately, there are 21 FDA approvals ([1][1]). Such a list is remarkable and does not include combinations of these agents. The 5-year survival

Endocrine Cancers: Defying the Paradigms

Endocrine cancers, studied for the boards and then largely forgotten by medical oncologists, comprise a set of rare but very interesting tumors with a diverse clinical spectrum. Few tumors are more aggressive than adrenocortical cancer or more lethal than anaplastic thyroid cancer. And few are more

Base Pairs to Populations

“There is much work to be done and many challenges exist in our mission to end the suffering that breast cancer brings.” So conclude Guest Editors Ann Partridge and Lisa Carey in their overview for this CCR Focus on breast cancer. Oncologists treating rare or treatment-refractory cancers, such