James F. Holland, MD, Distinguished Professor of Neoplastic Diseases, Mount Sinai School of Medicine, New York, has been at the forefront of cancer research for more than half a century. In a recent interview with The ASCO Post, Dr. Holland looked back at his research at NCI and explained why our accomplishments over the past several decades reinforce his concept that there are no incurable cancers, just precurable ones.

The Early Days

Combining cytotoxic agents was a significant conceptual hurdle in the early days of cancer research. Was there an early influence on the direction of your research?

When I went to the NCI in 1953, I was assigned to help Lloyd W. Law, PhD, prepare a lecture he was giving to the research directors of the NIH. It was the beginning of a rich learning experience that had a profound effect on my career. Dr. Law was a true pioneer, with two important discoveries to his credit that were instrumental in the development of medical oncology.

First, resistance preexists and represents the selection of a resistant cell out of a population rather than developing as a biochemical mechanism to resist chemotherapy. Second, combination chemotherapy is more effective than single drugs given in sequence because a combination enhances the potential for eradication. Cells resistant to drug A might in fact not be resistant to simultaneously given drug B.

When I was leaving NCI, Clinical Director Gordon Zubrod recruited Emil (Tom) Frei to fill my position. He introduced us, and Tom and I became lifelong colleagues and friends. We modified the in-house study that I had been conducting, and out of that friendship came the Cancer and Leukemia Group B (CALGB), originally called the Acute Leukemia Group B. We led the first cooperative group study in the United States, treating patients with acute leukemia with a combination chemotherapy regimen of mercaptopurine and methotrexate. At 55 years, CALGB is the oldest surviving cooperative group in the country. Also out of that friendship came Holland-Frei Cancer Medicine, now in its 8th edition.

Lessons for Today

What can we learn from your early days of research and how those pursuits differed from research today?

There was less red tape, and I can say assuredly that patient safety did not suffer for it. We were conceptually following a logical scientific premise with the idea that we would find useful clinical answers. And indeed we did, without the regulatory burdens that today’s lawyers in the House of Representatives and Senate have imposed, some of which is well-intentioned legislative overkill that doesn’t expand the boundaries of research or make patients on clinical trials any safer.

How would you characterize clinical trial accrual then and now?

In those days, acute leukemia was an incurable disease. The clinical trials we designed offered patients their best therapeutic options, often their only option. What parents wouldn’t want that for their child? So entering a clinical trial was not considered risky, it was considered an opportunity to get the newest available therapy. However, as our therapies get closer to success, each incremental benefit is usually less, and perhaps today people worry that entering a clinical trial might limit them from receiving an established treatment with proven efficacy. So, in the 1950s, we did not have that barrier to accrual because we were essentially offering patients their best chance for a positive outcome.

Advances in Cancer Biology

Over the past 2 decades, our understanding of tumor biology has increased at a breakneck pace. However, mortality rates from cancer remain high. Are you optimistic?

Absolutely. However, I personally think the phrases targeted or personalized therapies are slightly misleading. First off, the concept of specific targeting is not new. Targeting specific enzymes or receptors is simply more intelligent therapy.

Over the past decades we’ve unearthed the complexity of cancer biology, and as we venture deeper into its molecular components it will undoubtedly become even more complex. But for each bit of information we obtain about a particular gene, it clarifies a pathway that is either attackable today or that will be attackable in the near future. Moreover, understanding pathways and how to characterize and classify diseases is intrinsic to improving our ability to identify and treat the hundreds of different disease states in cancer. The reason for optimism is that we are breaking the cure barrier, albeit slowly. We are seeing more tumors that are curable, more subcurable tumors being treated successfully, and several precurable tumors that are showing signs of vulnerability to chemotherapy.

Cure vs Chronic Illness

Another contemporary concept is that we need to reach a point at which we manage cancer as a long-term chronic disease. What’s your perspective on that approach?

The prime objective is prevention. Once disease is present, the prime objective becomes cure. Longtime survival is meritorious as long as the patient’s quality of life is relatively good. And with some diseases this balance can be achieved. In metastatic cancer there are a few diseases, such as lymphoma, myeloma, and chronic myelogenous leukemia, where dramatic therapeutic advances have allowed patients to live without undo impact on their daily lives. But this is not true for metastatic lung, liver, colon, and other cancers, where the course of the illness is still measured in months or years, not decades. And as chronic illness for me carries the concept of decades, that formulation doesn’t work in other than the few cancers I mentioned.

So we do not want to settle for incomplete eradication. A number of cancers—choriocarcinoma, testis cancer, large-cell lymphomas, Hodgkin disease, and acute lymphocytic leukemia in children, to name a few—are curable with multimodality treatment options. We need to keep our eye on the target—curing people with cancer. The philosophical palliative of living longer with metastatic disease is not as important or realistic as is the effort at cure.

In 1976, when Bonadonna, Veronesi, and colleagues published their report on adjuvant CMF [cyclophosphamide, methotrexate, fluorouracil] for operable breast cancer in The New England Journal of Medicine, I was asked to write the editorial. I called their findings a monumental change in the treatment of breast cancer. Many in the community excoriated my assessment, calling it hyperbole, but in fact it proved true—we can cure a substantial portion of women who retrospectively must have had micrometastatic disease at the time of surgery because their survival is markedly better after chemotherapy than after placebo.

Thus, such women had disease, which at the microscopic level could be cured with adjuvant chemotherapy after surgery (or perhaps radiation) for their primary tumor. This paradigm offers opportunities for many other cancers. So I’m not an advocate of living with your cancer for a long period; I’m an advocate of getting rid of your cancer altogether.

Preventive Approaches

What are your thoughts on the advances we’ve seen in preventive vaccines such as that for human papillomavirus (HPV)?

The rate of cervical carcinoma in the United States has been decreasing for many years based on sexual hygiene, behavioral changes, and treatment of HPV infections. The concept of HPV immunization is valid (as is true for hepatitis B, particularly in Africa and countries without the advantages of the U.S. community), but I don’t know what impact it has had on cervical cancer rates. The incubation period from the time of infection to the development of cervical cancer might be 20 years. So we’ll have to wait for the data before we come to conclusions about immunization against cancer. Until then, increased awareness about known risk factors for developing cancer such as tobacco products, various pollutants, and dietary habits must still command medical attention.

Ongoing Research

What is a day in the life of James Holland like?

I still see patients a couple of days a week and go to clinic to teach Fellows, but my primary motivation is my research. My research partner, Dr. Beatriz Pogo, our colleagues, and I have identified a human mammary tumor virus (HMTV) in breast cancer that is 95% homologous to the mouse mammary tumor virus (MMTV) known to cause breast cancer in mice. The viral sequences are not in adjacent normal tissues, and thus are not genetically inherited, but rather, acquired. The virus is present in 30% to 40% of breast cancers in the Western world, where Mus domesticus (the common house mouse) is indigenous, with abundant MMTV in its genome. In Asia, where breast cancer is much less common, and different mouse species are indigenous, only 1% to 12% of breast cancers contain viral sequences. These data are consistent with a causal role for the virus, but we have not proven that postulate as yet. We are hard at work in this endeavor, however, and that is what keeps me going. ■