We are just completing the first quarter of 2015, and already there has been a series of exciting new treatment approvals offering new hope to patients with cancer.

The promise of PD-1 inhibition has officially reached patients with lung cancer with the approval of nivolumab (Opdivo) for the treatment of patients with advanced squamous non—small cell lung cancer who have progressed on or after platinum-based chemotherapy. The approval was announced 3 months ahead of the FDA’s scheduled decision date.

The FDA also recently approved the first US-authorized biosimilar, Zarxio (filgrastim-sndz), for all five authorized indications of its counterpart, the G-CSF analog Neupogen (filgrastim). Zarxio was the first product to be submitted and reviewed under the Biosimilar Pathway established by the federal government in 2010. The rationale behind the law is that expediting the approval of biosimilars will expand access and reduce costs. Let’s hope that promise is fulfilled as more of these products are added to the oncology armamentarium.

Other treatments approved in the recent flurry of FDA activity include lenvatinib (Lenvima) as a treatment for patients with progressive, radioactive iodine-refractory differentiated thyroid cancer, and lenalidomide (Revlimid) plus dexamethasone for newly diagnosed patients with multiple myeloma.

Beyond these new treatment options, this issue also includes highlights of emerging therapies discussed at the 2015 Genitourinary Cancer Symposium. Specifically, the anti—PD-L1 agent MPDL3280A, in combination with bevacizumab (Avastin), had strong antitumor activity and induced responses in 4 of 10 patients with metastatic renal cell carcinoma in an open-label phase Ib study (

). Additionally, combining the investigational vaccine PROSTVAC with the immune checkpoint inhibitor ipilimumab (Yervoy) may improve overall survival in metastatic castration-resistant prostate cancer, according to findings from a phase I study (

It’s been a great year in oncology so far. Let’s keep the momentum going! As always, thank you for reading. 

Articles

We are just completing the first quarter of 2015, and already there has been a series of exciting new treatment approvals offering new hope to patients with cancer.


New Approvals, New Hope

Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research

		John Theurer Cancer Center at Hackensack University Medical Center

Medicine has transformed at a dizzying pace over the last decade, much of it fueled by rapid advances in genomics and high throughput technology, particularly next-generation sequencing (NGS). While the first human genome took almost 7 years to complete at a cost of $3 billion, the same genome can now be sequenced in less than 2 weeks at a cost that will soon be under $1000.

 Since cancer is fundamentally a disorder of DNA, there has been growing angst amongst some anatomic pathologists that their traditional roles as diagnosticians will succumb to an army of DNA sequencers—the concern is that if tissue is collected by surgeons and interventional radiologists and directly sequenced, pathologists will be bypassed entirely.

These fears are unfounded. In fact, as high-throughput technology becomes more widely available, it will be integrated as a tool for pathologists and clinicians working together for better patient stratification and improved outcomes.

As Dr Juan Rosai, one of the greatest surgical pathologists of our time, has written, the amount of information gleaned from a single H&E slide is “staggering.” He argues that “the morphologic appearance of a tumor as seen in an H&E slide represents the grand synthesis of thousands of genes working in concert and sometimes in opposition, and there is probably not a single gene that plays an important role in the neoplastic process whose expression is not manifested in one way or another in a morphologic change that can be detected by those with the training and ability to do it.”

Traditional high-throughput molecular analysis, such as DNA sequencing or microarrays, starts by grinding up the tissue into a “mix,” which obscures the spatial components of the disease. Next-generation sequencing definitely benefits from a pathologist choosing the most appropriate tissue for testing and, in some cases, should use microdissection.

Depending on the chemistry employed by the NGS analyzer, the length of read, and the type of read (uni- vs bidirectional), NGS can have significant base-call error rates, leading to background noise.

 In specimens with low concentrations of tumor, this “noise” can mask low-level changes in DNA sequences. Accurate identification of the tumor tissue-of-origin and subtype classification is also a prerequisite for proper interpretation of molecular results.

The most common example is lung cancer, in which adenocarcinoma and small cell lung carcinoma (SCLC) are known to be biologically distinct. The finding of an EGFR mutation in a lung adenocarcinoma does confer increased sensitivity to EGFR tyrosine kinase inhibitors, while the same mutation has no (defined) such benefit in SCLC.

Similarly, while a BRAF V600E mutation may predict increased sensitivity to vemurafenib in melanoma, the same mutation abrogates the favorable outcome of anti-EGFR monoclonal antibodies in colorectal cancers that are wild-type KRAS.

 Clearly, the significance of any mutation must be interpreted in the context of morphology.

Finally, the presence of a mutation or an atypical molecular result may not be an indicator of malignancy. Multiple studies have shown that highly sensitive PCR techniques can detect the presence of a BCR-ABL transcript in up to 10% of healthy individuals who have no evidence of chronic myelogenous leukemia.

 Other studies have identified IGH/BCL2 translocations, the most common cytogenetic finding in follicular lymphoma, in up to 50% of peripheral blood of otherwise normal individuals.

 Such findings may become increasing common as new techniques become available to analyze minute quantities of cell-free DNA in plasma. Pathologists will be required to interpret and integrate these results as part of the overall diagnostic work-up.

The continued progress of cancer cell biology and rapidly advancing molecular techniques will continue to help define more precise subentities. The complexity of the results needs to be put in perspective of the overall diagnosis for its clinical significance. A few decades ago pathology diagnosis was based essentially on morphology, then came immunohistochemistry and flow cytometry, which changed the field and did not replace morphology. As expected, these technologies were progressively integrated into the full pathology analysis. No one nowadays would sign a report without IHC markers and/or flow cytometry results to confirm clonality or give prognostic information. Additional emerging technologies, such as digitalization of tissue, will help through automation both processing speed and quantification of components involved in morphology analysis.

The origins of pathology (Greek, pathologia: “study of emotions or suffering”) could perhaps date back to ancient physicians struggling through observations and philosophy while trying to unravel the mysteries of the human body and its afflictions. Pathologists in the molecular era, I would argue, will become critical in teaching and further guiding clinicians on how to interpret molecular findings and, as such, will be a central to the effort of precision medicine.

			National Human Genome Research Institute. “About About NHGRI: A Brief History and Timeline.” http://www.genome.gov/10001763. Accessed March 17, 2015.

			Rosai, J. The continuing role of morphology in the molecular age. 

			Wall, JD et al. Estimating genotype error rates from high-coverage next- generation sequence data. 

			Liu, L et al. Comparison of next-generation sequencing systems. 

			Cagle PT, Myers J. Precision medicine for lung cancer: role of the surgical pathologist. 

			Mao C et al. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. 

			Ismail SI et al. Incidence of bcr-abl fusion transcripts in healthy indi- viduals. Mol Med Rep. 2014;9(4):1271-1276.

			Paltiel O et al. Translocation t(14;18) in healthy individuals: preliminary study of its association with family history and agricultural expo- sure. 

Andre Goy, MD, discusses how pathologists will continue to play a critical role in oncology care, even with the technological advances of the molecular era.


Redefining the Role of Pathology in the Molecular Era: Away From the Microscope? Not So Fast

Targeted therapies have shown significant promise in oncology, improving survival and becoming the standard of care across multiple cancer types. But striving for true precision medicine in oncology by focusing on smaller and smaller tumor subtypes comes with its own set of challenges, according to Ruth O’Regan, MD.

O’Regan, formally a professor of Hematology and Medical Oncology at Emory University, was recently appointed the division head of Hematology, Medical Oncology, and Palliative Care in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health.

In an interview with Oncology & Biotech News, O’Regan discussed the many advantages and challenges of molecular subtyping as they related to her new position at the University of Wisconsin.

 What do you hope to achieve in your new role?

 The good news for me is that the faculty here is very strong and very productive, so that is positive. I think there are some areas in which we can improve, particularly in expanding our research. My biggest goal is to improve our clinical trials and expand the number that we do. I want to work with other institutions to further our clinical research.

Are there particular areas in which you want to expand clinical research/trials?

My focus is on breast cancer, but I think overall we’d like to focus on therapeutic trials across all cancers and try and work with other institutions. We already have a trial network here called the Wisconsin Oncology Network (WON) and I think we’d like to work to increase the number of trials being done through that group because it really spans throughout the whole state. It is a unique resource that we’d like to take advantage of more.

Your new role encompasses solid tumors as well as blood cancers. Do you see any overarching challenges across the board regarding the treatment of both?

I think for everyone globally one of the things we struggle with is that we’ve become so complex in our understanding of different cancers. Nothing is just one cancer type; there are multiple subtypes of each cancer. And the problem with that is when clinical trials become available they are so specific to different subtypes, only a small group of people qualifies and you only see a group of patients occasionally. I think we all struggle with the cost of opening a trial and then not being able to accrue many patients on the trials we would like. That is the cost of molecular subtyping.

The only way you can do it is by collaboration with other institutions, both nationally and internationally. We are very interested in working with other institutions across the country to accrue these more specific trials. It is a complex issue, but by working with others we can address these questions.

We do need to hone in on the specific subtypes of cancers so that we are only giving an individual patient what they need for the cancer that they have instead of giving them something that isn’t going to work. It is all about tailoring treatment. The challenge is figuring out which patients with which cancers really benefit the most from that approach. I think across the board—from targeted agents, chemotherapy agents, immunotherapies&mdash;we just have to really do a better job of working out who is going to benefit.

We need to do the right preclinical studies before we bring new drugs to patients so that we have some idea of who is going to benefit from those drugs.

What research at the University of Wisconsin School of Medicine are you particularly excited about?

We have a very active phase I program, which has been around for a long time. Even in phase I programs, we are looking at very specific patients. There is a lot of strength in a number of areas here. We have a very active imaging program for preclinical work, and there is a lot happening in the liquid biopsy space. We are looking at circulating tumor cells and using them to be able to predict why a patient would respond to one treatment versus another. I am still learning everything that is going on here, but what I have seen so far has been really interesting and very impressive.

Are you going to be continuing your own research at this new institution?

Yes, the plan is to continue my focus on breast can- cers that are resistant to current therapies and I will probably retain the focus that I had on triple-negative breast cancer at Emory. I am excited to work with some of the breast cancer researchers who are here to expand that. I am trying to bring some of the trials I was doing at Emory to the University of Wisconsin.

So, do you have time in your life for anything other than your work?

I really enjoy traveling and I am just looking forward to settling in here in Wisconsin after moving from Georgia (where Emory is located). I actually lived in Milwaukee when I first came to the United States from Ireland, so I am familiar with Wisconsin. I haven’t quite worked out what do with the winters here yet, but I am hoping to really get into some outdoor activities here once I do.

Ruth O'Regan, formally a professor of Hematology and Medical Oncology at Emory University, was recently appointed the division head of Hematology, Medical Oncology, and Palliative Care in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health.

March 2015 | Oncology & Biotech News

New Approvals, New Hope

Redefining the Role of Pathology in the Molecular Era: Away From the Microscope? Not So Fast

O'Regan Joins Leadership at University of Wisconsin School of Medicine