March 2020 Edition Vol.12, Issue 3

An Interview with Azra Raza, MD, Oncologist, Scientist and Author

Dr. Azra Raza is the Chan Soon-Shiong Professor of Medicine and Director of the MDS Center, Columbia University Medical Center (CUMC) in New York City.  A practicing oncologist who sees 30 to 40 cancer patients weekly, her life is devoted to the early detection and prevention of cancer. Dr. Raza also directs a basic cancer research lab at Columbia that has generated hundreds of original publications for high profile scientific journals.  

Published in October 2019, Dr. Raza’s book, The First Cell: And the Human Costs of Pursuing Cancer to the Last, has attracted significant attention. It explores the reasons she feels there should be a paradigm shift in cancer care. 

Along with her research, Dr. Raza has spent her career treating patients with advanced blood cancers, many of whom have a low likelihood of survival. Her experience has led her to consider strategies that will increase the emphasis on early detection, redirecting the vast resources now devoted to modest improvements in survival in late-stage disease.

In this OBR interview, edited and condensed for brevity, we asked Dr. Raza to describe what changes she feels are needed in cancer care, what specific solutions she proposes, and how her book has been received.

OBR: By newspaper reports, one has to assume that there has been enormous progress in oncology. Why do you see a need for change?

Dr. Raza: Let’s start with numbers. Cancer mortality has come down about 1% per year for the last 30 years, but this largely reflects the decline in smoking and strategies for earlier detection of cancer. It is true that we are curing 68% of patients with cancer, but these are the patients with early disease who are being treated with the same combinations of surgery, chemotherapy, and radiation we have been using for decades. I call this the slash-poison-burn approach, and it does not generally work in late stages of cancer. 

We have seen some recent advances in late-stage cancer, but they are very expensive and only effective in a small proportion of patients. With thousands of brilliant researchers and millions of published papers, we need to ask ourselves why we have not done better. In the book I discuss an acronym, CRUSH, that covers the problems I see.

OBR: Can you take us through these issues?

Dr. Raza:  The C stands for complexity. Cancer starts as a single cell, but it becomes more complex with every cell division. A collaborative sequencing project that evaluated more than 2,000 tissue samples from 38 cancers demonstrated that the same cancer has mutations that not only differ from patient to patient but even from tumor to tumor within the same patient and then from clone to clone within the same tumor. There are at least four to five mutations, on average, participating in the pathology of advanced cancer, often with thousands of passenger mutations. Cancer is constantly evolving right in front of us.

OBR: But this complexity is fairly well appreciated at this point, isn’t it?

Dr. Raza: Yes, but researchers continue to pursue a reductionist approach. This is the R in my acronym. From the beginning, researchers have been enamored with finding a single gene that explains what is going wrong, but we know now that it is not a question of a single gene, particularly in patients with advanced disease. The exceptions, like chronic myeloid leukemia, are rare. 

Although the slash-poison-burn approach can be effective in early stages of disease, the potential for meaningful benefits by targeting individual pathways in late stage disease is very low. 

Once we understand every signaling pathway, perhaps we can develop treatments with curative potential, but that is not going to happen anytime soon. By one estimate, it will take more than a thousand years to work out all possible pathways of disease progression. 

I think it is time we take the blinders off and look at the problem realistically. In other words, I think the only real chance to improve outcomes is changing our focus to early diagnosis. Right now less than 5% of research funding is going to early detection even though there are promising technologies to move this area forward. 

OBR: And the other letters in the acronym?

Dr. Raza: The U in CRUSH stands for ultra hype. We read all the time about great victories and game-changing advances, but these terms are typically employed for treatments that offer relatively modest survival gains at enormous cost. For most of the cancers we treat, we are still stuck in the slash-poison-burn paradigm, and we continue to look for advances with simplistic testing methods. 

This is the S in the CRUSH acronym. With the simplistic in vitro and animal protocols we have been using for decades, the failure rate for drugs brought to clinical trials is 95%. Of the 5% that are considered a success and receive regulatory approval, the median survival improvement is five months. 

OBR: And the letter H?

Dr. Raza: The letter H stands for high financial burden of the treatments we are using in late stage cancer. In the United States, 42% of cancer patients are financially ruined within two years of starting cancer treatment. Even in the rare cases where important new therapies do provide meaningful survival advances, the costs of treatment are not sustainable. 

CAR T cells are an example in my own field. Of the relatively small number of candidates, many of the subset that responds without a fatal toxicity will be financially ruined by the treatment. You have to question this kind of success.

OBR: You have spoken about what is wrong, but what is the solution?

Dr. Raza: Earlier detection of cancer with tools such as mammography, PSA testing, and colonoscopy have been one source of improved survival, but we can do better.  With the important progress that has been made in genomics, proteomics, transcriptomics, and metabolomics, we are seeing very sensitive methods for detecting cancer early and inexpensively. 

Liquid biopsies, meaning blood sample analysis, can now identify 13 solid cancers at early stages. One company recently announced that it is detecting multiple cancers with microRNA from a single drop of blood. There are many leaders in this field, including Dr. Sam Gambhir at the Canary Center for Cancer Early Detection at Stanford University, Dr. Bert Vogelstein at the Ludwig Center at Johns Hopkins, and Dr. Leroy Hood at the Institutes of System Biology in Seattle. 

Many of the emerging technologies might change the way we practice. Sam Gambhir, for example, is working on a magnetic wire that when threaded into the vein can attract circulating tumor cells. This is a tool that might be used periodically in healthy individuals for detection of cancer at its earliest stages. 

These technologies deserve to be the source of real excitement and real optimism, representing a paradigm shift for the future. As we go to earlier detection, our traditional slash-poison-burn therapies will provide more cures but so will many of the targeted therapies that are now failing in advanced disease.

OBR: Many of the reviews of your book, like the one in the New York Times, have praised it and your ideas, but suggest that you are dismissing important advances unjustifiably.

Dr. Raza: This has surprised me. I am voicing my frustration as an oncologist, as a scientist, and as a widow of a cancer patient. When I began treating acute myeloid leukemia (AML) in 1977, I used a two-drug chemotherapy combination commonly known as 7+3. I am still using these same drugs. I have been treating cancer patients for 35 years, but by 1984 I realized that if I really want to cure AML, I will have to treat the pre-leukemic state. 

I have now collected longitudinally 60,000 samples from thousands of patients as they progress through the natural history of disease, and I believe these types of samples, much more than animal models, can provide the information we need for curing disease.  

Like others, I am excited when there are important advances in late stage disease, but it is time for all of us to stop fooling ourselves. If we look honestly at where we have had the most success, it has been in early cancer detection and treatment. We need to shift our focus here, because there is a far greater likelihood of treatment success. 

There is no need for anyone to be offended by this message. I am not disparaging the efforts to develop new treatments, such as immunotherapies, for late stage disease, but I believe the real gains in cancer will come from prevention and early detection. 

It is likely that no one method of early detection will work. Rather, it will be a combination of imaging, biomarkers, and learning, with the help of artificial intelligence, from big data. However, due to the low likelihood that any advance in late stage disease will have an important impact on survival, we need to change the paradigm.

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